Is DYSF p.Arg492Ser (c.1476G>C) pathogenic?

DYSF p.Arg492Ser (c.1476G>C) is classified Uncertain significance in DYSF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-16). AlphaMissense: likely pathogenic (0.6619); Very rare (popmax 0.005%, amr); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Arg492Ser (c.1476G>C) in the general population?

DYSF p.Arg492Ser (c.1476G>C) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about DYSF p.Arg492Ser (c.1476G>C)?

AlphaMissense predicts likely pathogenic (score 0.6619) — an in-silico prediction, not a clinical call.

DYSF p.Arg492Ser

Q: What condition is associated with DYSF p.Arg492Ser (c.1476G>C)?

DYSF p.Arg492Ser (c.1476G>C) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.1476G>C · rs768604446 · VCV1931515

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.6619	likely pathogenic
REVEL	0.393	indeterminate
SaProt	LLR -10.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.22	acceptor loss · deltas
Pangolin	Δ0.28	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.5	GERP -1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R460S vs ClinVar R492S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,038 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000205% 3/1,461,890 alleles · very rare

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.Arg492Ser
Coding: c.1476G>C
MANE Select: NM_001130987
dbSNP: rs768604446
Type: single nucleotide variant
Location: chr2:71535294 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 492: the c2 3 domain

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

Similar variants

DYSF p.Arg492= Likely benign ★ same residue
DYSF p.Arg492del Likely pathogenic ★★ 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+4A>G Pathogenic ★★★ same condition
DYSF c.1276+5G>A 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-arg492ser (accessed [today's date]).

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