Is DYSF p.Pro1232Leu (c.3695C>T) pathogenic?

DYSF p.Pro1232Leu (c.3695C>T) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.0839); Rare (popmax 0.132%, mid); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

What condition is associated with DYSF p.Pro1232Leu (c.3695C>T)?

DYSF p.Pro1232Leu (c.3695C>T) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin, autosomal recessive limb-girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset (ClinVar).

How common is DYSF p.Pro1232Leu (c.3695C>T) in the general population?

DYSF p.Pro1232Leu (c.3695C>T) is rare (popmax 0.132%, mid) (gnomAD).

What do computational predictors say about DYSF p.Pro1232Leu (c.3695C>T)?

AlphaMissense predicts likely benign (score 0.0839) — an in-silico prediction, not a clinical call.

DYSF p.Pro1232Leu

c.3695C>T · rs150942486 · VCV452908

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0839 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.0839	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -9.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.84	GERP 1.1, phastCons 0.27
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	16.87	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 P1214L vs ClinVar P1232L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.132% Middle Eastern · 8/6,062 alleles

Filtering AF 0.0893% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0829%

Overall 0.0239% 385/1,613,990 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	758
South Asian	0.106%	939
Remaining individualsnot grpmax-eligible	0.032%	3,125
European (non-Finnish)	0.0199%	5,021
African / African-American	0.0173%	5,773
Admixed American	0.01%	10,004
Finnishnot grpmax-eligible	0.00783%	12,767
East Asian	0.00223%	44,882

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.Pro1232Leu
Coding: c.3695C>T
MANE Select: NM_001130987
dbSNP: rs150942486
Type: single nucleotide variant
Location: chr2:71598684 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1232: a binding site; the c2 4 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 distal myopathy with anterior tibial onset Miyoshi muscular dystrophy 1

Similar variants

DYSF p.Pro1232= Likely benign ★★ same residue
DYSF p.Pro1232Arg 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-pro1232leu (accessed [today's date]).

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