R685H
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialArginine → Histidine at position 685 — SAME position as R685P (Atlas card flagship pathogenic-stabilising variant) and R685C. ClinVar Conflicting with broad spectrum — Wolfram, Cataract 41, DFNA6. AlphaMissense 0.12 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.18 (substantial).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | N682 | N682 | Preserved |
| Hydrogen bond | I688 | I688 | Preserved |
| Hydrogen bond | L689 | L689 | Preserved |
| Polar contact | N682 | N682 | Preserved |
| Polar contact | M683 | M683 | Preserved |
| Polar contact | I688 | I688 | Preserved |
| Polar contact | L689 | L689 | Preserved |
| Van der Waals | M683 | M683 | Preserved |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Hearing loss, inheritance unstated (inheritance not specified). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome; Wolfram-like syndrome
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Hearing impairment
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in Middle Eastern: AF 0.033% (2 of 6,084 alleles), 2.0x the global figure. The global AF describes the general population, not the at-risk group.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| Middle Eastern | 0.033% | 2 / 6,084 | 0 | ~1 in 1520 |
| European (non-Finnish) | 0.019% | 221 / 1,179,928 | 0 | ~1 in 2670 |
| Admixed American | 0.015% | 9 / 60,016 | 0 | ~1 in 3330 |
| Remaining individuals | 0.013% | 8 / 62,460 | 0 | ~1 in 3900 |
| African / African American | 0.012% | 9 / 74,934 | 0 | ~1 in 4160 |
| East Asian | 0.0089% | 4 / 44,888 | 0 | ~1 in 5610 |
| Finnish | 0.0064% | 4 / 62,826 | 0 | ~1 in 7850 |
| South Asian | 0.0033% | 3 / 91,086 | 0 | ~1 in 15180 |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
Structural Context
Position 685 same neighbors as R685P/R685C: THR686 (2.5 Å), ALA684 (2.5 Å — A684T/V/G), ASN682 (3.5 Å), MET683 (4.3 Å), GLN687 (4.4 Å — Q687H).
R685H is the THIRD substitution at position 685 (with R685P, R685C). Partial charge reduction. |ΔΔG| 1.18 substantial; AM 0.12 under-call; multi-phenotype confirms.
Druggability Assessment
Mechanism: partial charge loss in the dense 684-688 cluster. Therapeutic: same cluster target as R685P, R685C, A684T/V/G, Q687H.
Why this matters
Feed this card to Wolfram Intelligence
Download the R685H PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.