Is DYSF p.Arg762His (c.2285G>A) pathogenic?

DYSF p.Arg762His (c.2285G>A) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-25). AlphaMissense: ambiguous (0.4101); Very rare (popmax 0.00667%, amr); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Arg762His (c.2285G>A) in the general population?

DYSF p.Arg762His (c.2285G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about DYSF p.Arg762His (c.2285G>A)?

AlphaMissense predicts ambiguous (score 0.4101) — an in-silico prediction, not a clinical call.

DYSF p.Arg762His

Q: What condition is associated with DYSF p.Arg762His (c.2285G>A)?

DYSF p.Arg762His (c.2285G>A) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin, autosomal recessive limb-girdle muscular dystrophy type 2B (ClinVar).

c.2285G>A · rs759015457 · VCV859751

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.4101	ambiguous
REVEL	0.905	moderately pathogenic-leaning
SaProt	LLR -7.23	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 18 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R744H vs ClinVar R762H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,992 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00211% 34/1,614,026 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,998
South Asian	0.00549%	18,216
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
African / African-American	0.00267%	37,447
East Asian	0.00223%	44,892
European (non-Finnish)	0.00169%	59,002
Remaining individualsnot grpmax-eligible	0.0016%	62,486

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DYSF
Protein: p.Arg762His
Coding: c.2285G>A
MANE Select: NM_001130987
dbSNP: rs759015457
Type: single nucleotide variant
Location: chr2:71561820 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB

Full DYSF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuromuscular disease caused by qualitative or quantitative defects of dysferlin — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2B

Similar variants

DYSF p.Arg762Cys Uncertain significance ★★ ⚠ same residue
DYSF p.Arg762= Likely benign ★ same residue
DYSF c.1003-3C>A Pathogenic ★★★ same condition
DYSF c.1033+1G>A Pathogenic ★★★ same condition
DYSF c.1033+4A>T Likely pathogenic ★★★ same condition
DYSF c.1149+1G>A Pathogenic ★★★ same condition
DYSF c.1149+1G>C Pathogenic ★★★ same condition
DYSF c.1149+4A>G Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dysf-p-arg762his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown