Is DYSF p.Pro135Leu (c.404C>T) pathogenic?

DYSF p.Pro135Leu (c.404C>T) is classified Likely benign in DYSF (ClinVar, Expert panel, 6 submitters; last evaluated 2025-06-17). AlphaMissense: likely benign (0.068); Very rare (popmax 0.00683%, afr); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Pro135Leu (c.404C>T) in the general population?

DYSF p.Pro135Leu (c.404C>T) is very rare (popmax 0.00683%, afr) (gnomAD).

What do computational predictors say about DYSF p.Pro135Leu (c.404C>T)?

AlphaMissense predicts likely benign (score 0.068) — an in-silico prediction, not a clinical call.

DYSF p.Pro135Leu

Q: What condition is associated with DYSF p.Pro135Leu (c.404C>T)?

DYSF p.Pro135Leu (c.404C>T) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.404C>T · rs773837400 · VCV284579

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.068 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00683%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

Likely Benign for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):

BP2

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.401C>T variant in DYSF, which is also known as NM_001130987.2: c.404C>T p.(Pro135Leu), is a missense variant predicted to cause substitution of proline by leucine at amino acid 134, p.(Pro134Leu). This variant has been observed in two individuals with features consistent with LGMD (PMID: 36983702; 23406536; 30564623; LOVD Individual #00222735); however, in both cases it was identified in cis with a null variant, including one classified as pathogenic by the ClinGen LGMD VCEP (NM_003494.4: c.5022del p.(Phe1674LeufsTer48), PMID: 36983702) (BP2; PP4 and PM3 not applicable). The filtering allele frequency of this variant is 0.0001865 in gnomAD v4.1.0 genomes (the upper threshold of the 95% CI of 3/41580 African/African American chromosomes), which is greater than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001) (PM2 not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed that the Pro134Leu protein reached the cell membrane, indicating no significant impact on this aspect of protein function (PMID: 35028538; BS3 not met). The computational predictor REVEL gives a score of 0.15, which is above the LGMD VCEP threshold of ≤0.1 for BP4 (criterion not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/17/2025): BP2.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.068	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -7.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1.7, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	22.7	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 P134L vs ClinVar P135L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00683% African / African-American · 5/73,178 alleles

Filtering AF 0.0026% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00165%

Overall 0.00103% 16/1,551,696 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00683%	14,636
Remaining individualsnot grpmax-eligible	0.00166%	60,124
South Asian	0.00119%	84,058
European (non-Finnish)	0.000785%	127,442

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.Pro135Leu
Coding: c.404C>T
MANE Select: NM_001130987
dbSNP: rs773837400
Type: single nucleotide variant
Location: chr2:71511865 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 135: the 'disordered' region

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

Disease context

autosomal recessive limb-girdle muscular dystrophy — 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.Pro135= Conflicting classifications of pathogenicity ★ same residue
DYSF p.Pro135fs Pathogenic ★ 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.1033+5G>A Likely pathogenic ★★★ same condition
DYSF c.1149+1G>A Pathogenic ★★★ same condition
DYSF c.1149+1G>C 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-pro135leu (accessed [today's date]).

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