Is DYSF p.Val258Met (c.772G>A) pathogenic?

DYSF p.Val258Met (c.772G>A) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2024-10-31). AlphaMissense: likely pathogenic (0.6041); Ultra-rare (popmax 0.0258%, nfe); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Val258Met (c.772G>A) in the general population?

DYSF p.Val258Met (c.772G>A) is ultra-rare (popmax 0.0258%, nfe) (gnomAD).

What do computational predictors say about DYSF p.Val258Met (c.772G>A)?

AlphaMissense predicts likely pathogenic (score 0.6041) — an in-silico prediction, not a clinical call.

DYSF p.Val258Met

Q: What condition is associated with DYSF p.Val258Met (c.772G>A)?

DYSF p.Val258Met (c.772G>A) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin, autosomal recessive limb-girdle muscular dystrophy type 2B (ClinVar).

c.772G>A · rs150345121 · VCV259085

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.6041 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0258%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.6041	likely pathogenic
REVEL	0.691	pathogenic-leaning
SaProt	LLR -11.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	27.9	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 V226M vs ClinVar V258M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0258% European (non-Finnish) · 304/1,179,900 alleles

Filtering AF 0.0233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0224%

Overall 0.0203% 328/1,613,910 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0258%	3,881
Remaining individualsnot grpmax-eligible	0.0176%	5,682
Admixed American	0.0133%	7,501
African / African-American	0.00667%	14,997

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.Val258Met
Coding: c.772G>A
MANE Select: NM_001130987
dbSNP: rs150345121
Type: single nucleotide variant
Location: chr2:71515635 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 258: a β-strand; the c2 2 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

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

Similar variants

DYSF p.Val258= 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
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-val258met (accessed [today's date]).

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