Is DYSF p.Ala94Pro (c.280G>C) pathogenic?

DYSF p.Ala94Pro (c.280G>C) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-05-19). AlphaMissense: ambiguous (0.3441); Ultra-rare (popmax 0.015%, amr); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Ala94Pro (c.280G>C) in the general population?

DYSF p.Ala94Pro (c.280G>C) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about DYSF p.Ala94Pro (c.280G>C)?

AlphaMissense predicts ambiguous (score 0.3441) — an in-silico prediction, not a clinical call.

DYSF p.Ala94Pro

Q: What condition is associated with DYSF p.Ala94Pro (c.280G>C)?

DYSF p.Ala94Pro (c.280G>C) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin, autosomal recessive limb-girdle muscular dystrophy type 2B (ClinVar).

c.280G>C · rs759171890 · VCV538625

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3441 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, 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	0.3441	ambiguous
REVEL	0.168	moderately benign-leaning
SaProt	LLR -11.10	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.56	GERP -2, phastCons 0.031
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	19.5	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 A93P vs ClinVar A94P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/60,018 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.000616% 9/1,461,852 alleles · ultra-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.Ala94Pro
Coding: c.280G>C
MANE Select: NM_001130987
dbSNP: rs759171890
Type: single nucleotide variant
Location: chr2:71503254 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 94: the c2 1 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.Ala94Thr Uncertain significance ★★ ⚠ same residue
DYSF p.Ala94_Ala100dup Uncertain significance ★★ 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-ala94pro (accessed [today's date]).

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