Is DYSF p.Pro1239Leu (c.3716C>T) pathogenic?

DYSF p.Pro1239Leu (c.3716C>T) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-03-17). AlphaMissense: likely benign (0.1738); Ultra-rare (popmax 0.0146%, nfe); Associated with Inborn genetic diseases.

How common is DYSF p.Pro1239Leu (c.3716C>T) in the general population?

DYSF p.Pro1239Leu (c.3716C>T) is ultra-rare (popmax 0.0146%, nfe) (gnomAD).

What do computational predictors say about DYSF p.Pro1239Leu (c.3716C>T)?

AlphaMissense predicts likely benign (score 0.1738) — an in-silico prediction, not a clinical call.

DYSF p.Pro1239Leu

Q: What condition is associated with DYSF p.Pro1239Leu (c.3716C>T)?

DYSF p.Pro1239Leu (c.3716C>T) is associated with Inborn genetic diseases, autosomal recessive limb-girdle muscular dystrophy type 2B, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.3716C>T · rs368556029 · VCV499227

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0146%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1738	likely benign
REVEL	0.529	indeterminate
SaProt	LLR -6.34	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 4.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1221L vs ClinVar P1239L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0146% European (non-Finnish) · 172/1,179,964 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.0114% 184/1,613,492 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0146%	6,860
Remaining individualsnot grpmax-eligible	0.0144%	6,942
East Asian	0.00223%	44,886
African / African-American	0.00134%	74,902
South Asian	0.0011%	91,078

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.Pro1239Leu
Coding: c.3716C>T
MANE Select: NM_001130987
dbSNP: rs368556029
Type: single nucleotide variant
Location: chr2:71598705 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1239: a β-strand; the c2 4 domain

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

Disease context

Inborn genetic diseases — 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.Pro1239= 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-pro1239leu (accessed [today's date]).

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