Is DYSF p.Leu1246Pro (c.3737T>C) pathogenic?

DYSF p.Leu1246Pro (c.3737T>C) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2021-09-06). AlphaMissense: likely pathogenic (0.9816); Absent from gnomAD v4.1; Associated with Abnormality of the musculature.

How common is DYSF p.Leu1246Pro (c.3737T>C) in the general population?

DYSF p.Leu1246Pro (c.3737T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYSF p.Leu1246Pro (c.3737T>C)?

AlphaMissense predicts likely pathogenic (score 0.9816) — an in-silico prediction, not a clinical call.

DYSF p.Leu1246Pro

Q: What condition is associated with DYSF p.Leu1246Pro (c.3737T>C)?

DYSF p.Leu1246Pro (c.3737T>C) is associated with Abnormality of the musculature, autosomal recessive limb-girdle muscular dystrophy type 2B, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.3737T>C · rs2152855991 · VCV1180667

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9816 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Abnormality of the musculature

Computational evidence

Protein change
AlphaMissense	0.9816	likely pathogenic · top 5% in DYSF
REVEL	0.9	moderately pathogenic-leaning
SaProt	LLR -15.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	26.5	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 L1228P vs ClinVar L1246P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DYSF
Protein: p.Leu1246Pro
Coding: c.3737T>C
MANE Select: NM_001130987
dbSNP: rs2152855991
Type: single nucleotide variant
Location: chr2:71598726 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1246: the c2 4 domain

Full DYSF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Abnormality of the musculature — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2B neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Similar variants

DYSF p.Leu1246= 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-leu1246pro (accessed [today's date]).

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