Is DYSF p.Ser503Leu (c.1508C>T) pathogenic?

DYSF p.Ser503Leu (c.1508C>T) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-16). AlphaMissense: likely benign (0.0724); Ultra-rare (popmax 0.048%, afr); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Ser503Leu (c.1508C>T) in the general population?

DYSF p.Ser503Leu (c.1508C>T) is ultra-rare (popmax 0.048%, afr) (gnomAD).

What do computational predictors say about DYSF p.Ser503Leu (c.1508C>T)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

DYSF p.Ser503Leu

Q: What condition is associated with DYSF p.Ser503Leu (c.1508C>T)?

DYSF p.Ser503Leu (c.1508C>T) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin, autosomal recessive limb-girdle muscular dystrophy type 2B (ClinVar).

c.1508C>T · rs144931729 · VCV582717

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.048%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.42	acceptor loss, 27 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 2.2	GERP 0.72, phastCons 0.14
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	17.42	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.048% African / African-American · 36/74,940 alleles

Filtering AF 0.0357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.00459% 74/1,612,536 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.048%	2,082
Admixed American	0.00835%	11,983
South Asian	0.00662%	15,114
Remaining individualsnot grpmax-eligible	0.0032%	31,227
East Asian	0.00223%	44,854
European (non-Finnish)	0.00204%	49,134

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.Ser503Leu
Coding: c.1508C>T
MANE Select: NM_001130987 · reported on NM_003494
dbSNP: rs144931729
Type: single nucleotide variant
Location: chr2:71549377 (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.Ser503Trp 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
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-ser503leu (accessed [today's date]).

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