Is DYSF p.Pro144Leu (c.431C>T) pathogenic?

DYSF p.Pro144Leu (c.431C>T) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-09). AlphaMissense: likely benign (0.0805); Ultra-rare (popmax 0.0513%, mid); Associated with Miyoshi muscular dystrophy 1.

What condition is associated with DYSF p.Pro144Leu (c.431C>T)?

DYSF p.Pro144Leu (c.431C>T) is associated with Miyoshi muscular dystrophy 1, autosomal recessive limb-girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset (ClinVar).

How common is DYSF p.Pro144Leu (c.431C>T) in the general population?

DYSF p.Pro144Leu (c.431C>T) is ultra-rare (popmax 0.0513%, mid) (gnomAD).

How is Miyoshi myopathy inherited?

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

What do computational predictors say about DYSF p.Pro144Leu (c.431C>T)?

AlphaMissense predicts likely benign (score 0.0805) — an in-silico prediction, not a clinical call.

DYSF p.Pro144Leu

c.431C>T · rs139654844 · VCV897270

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0805 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0513%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Miyoshi muscular dystrophy 1

Computational evidence

Protein change
AlphaMissense	0.0805	likely benign
REVEL	0.35	indeterminate
SaProt	LLR -7.33	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 3.9	GERP 0.68, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	23.3	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 P143L vs ClinVar P144L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0513% Middle Eastern · 3/5,846 alleles

Filtering AF 0.0139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00744%

Overall 0.00206% 32/1,551,284 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0513%	1,949
Remaining individualsnot grpmax-eligible	0.00666%	15,026
Admixed American	0.00392%	25,506
South Asian	0.00357%	28,009
European (non-Finnish)	0.00174%	57,338

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.Pro144Leu
Coding: c.431C>T
MANE Select: NM_001130987
dbSNP: rs139654844
Type: single nucleotide variant
Location: chr2:71511892 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 144: the 'disordered' region

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

Disease context

Miyoshi muscular dystrophy 1 — 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 neuromuscular disease caused by qualitative or quantitative defects of dysferlin

For Miyoshi myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult
Prevalence: 1-9 / 1 000 000 (Japan)

Similar variants

DYSF p.Pro144Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
DYSF p.Pro144= Likely benign ★ same residue
DYSF p.Pro144fs Likely 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.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-pro144leu (accessed [today's date]).

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