Is DYSF p.Pro952Leu (c.2855C>T) pathogenic?

DYSF p.Pro952Leu (c.2855C>T) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-04). AlphaMissense: ambiguous (0.4304); Ultra-rare (popmax 0.0305%, nfe); Associated with distal myopathy with anterior tibial onset.

How common is DYSF p.Pro952Leu (c.2855C>T) in the general population?

DYSF p.Pro952Leu (c.2855C>T) is ultra-rare (popmax 0.0305%, nfe) (gnomAD).

How is Distal myopathy with anterior tibial onset inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DYSF p.Pro952Leu (c.2855C>T)?

AlphaMissense predicts ambiguous (score 0.4304) — an in-silico prediction, not a clinical call.

DYSF p.Pro952Leu

Q: What condition is associated with DYSF p.Pro952Leu (c.2855C>T)?

DYSF p.Pro952Leu (c.2855C>T) is associated with distal myopathy with anterior tibial onset, autosomal recessive limb-girdle muscular dystrophy type 2B, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.2855C>T · rs150717638 · VCV290702

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4304 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0305%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

distal myopathy with anterior tibial onset

Computational evidence

Protein change
AlphaMissense	0.4304	ambiguous
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -6.76	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 18 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	26.3	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 P934L vs ClinVar P952L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0305% European (non-Finnish) · 360/1,179,966 alleles

Filtering AF 0.0279% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0268%

Overall 0.0239% 385/1,613,936 alleles · ultra-rare exomes 365/1,461,782 · genomes 20/152,154 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0305%	3,278
Remaining individualsnot grpmax-eligible	0.0176%	5,680
Admixed American	0.00667%	15,001
African / African-American	0.00534%	18,733
East Asian	0.00446%	22,437
South Asian	0.00329%	30,357
Finnishnot grpmax-eligible	0.00156%	64,014

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.Pro952Leu
Coding: c.2855C>T
MANE Select: NM_001130987
dbSNP: rs150717638
Type: single nucleotide variant
Location: chr2:71568329 (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

distal myopathy with anterior tibial onset — 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 Miyoshi muscular dystrophy 1

For Distal myopathy with anterior tibial onset (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult

Similar variants

DYSF p.Pro952= Benign/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-pro952leu (accessed [today's date]).

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