Is DYSF p.Ser515Trp (c.1544C>G) pathogenic?

DYSF p.Ser515Trp (c.1544C>G) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-13). AlphaMissense: likely pathogenic (0.697); Ultra-rare (popmax 0.0209%, sas); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Ser515Trp (c.1544C>G) in the general population?

DYSF p.Ser515Trp (c.1544C>G) is ultra-rare (popmax 0.0209%, sas) (gnomAD).

What do computational predictors say about DYSF p.Ser515Trp (c.1544C>G)?

AlphaMissense predicts likely pathogenic (score 0.697) — an in-silico prediction, not a clinical call.

DYSF p.Ser515Trp

Q: What condition is associated with DYSF p.Ser515Trp (c.1544C>G)?

DYSF p.Ser515Trp (c.1544C>G) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.1544C>G · rs139258703 · VCV2191355

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.697 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.697	likely pathogenic
REVEL	0.736	pathogenic-leaning
SaProt	LLR -10.11	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 5.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	25.5	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 S483W vs ClinVar S515W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0209% South Asian · 19/91,074 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00137% 20/1,461,864 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0209%	4,793
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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.Ser515Trp
Coding: c.1544C>G
MANE Select: NM_001130987
dbSNP: rs139258703
Type: single nucleotide variant
Location: chr2:71539207 (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

Similar variants

DYSF p.Ser515Ter Pathogenic ★★ same residue
DYSF p.Ser515= Conflicting classifications of pathogenicity ★ same residue
DYSF p.Ser515Leu Conflicting classifications of pathogenicity ★ 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

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-ser515trp (accessed [today's date]).

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