Is DYSF p.Pro1801Leu (c.5402C>T) pathogenic?

DYSF p.Pro1801Leu (c.5402C>T) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.1389); Very rare (popmax 0.00659%, sas); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Pro1801Leu (c.5402C>T) in the general population?

DYSF p.Pro1801Leu (c.5402C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about DYSF p.Pro1801Leu (c.5402C>T)?

AlphaMissense predicts likely benign (score 0.1389) — an in-silico prediction, not a clinical call.

DYSF p.Pro1801Leu

Q: What condition is associated with DYSF p.Pro1801Leu (c.5402C>T)?

DYSF p.Pro1801Leu (c.5402C>T) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.5402C>T · rs371189093 · VCV897607

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1389 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.1389	likely benign
REVEL	0.627	indeterminate
SaProt	LLR -11.42	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	25.0	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 P1762L vs ClinVar P1801L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,084 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00118% 19/1,614,026 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,181
Remaining individualsnot grpmax-eligible	0.0048%	20,828
Admixed American	0.00333%	30,003
African / African-American	0.00267%	37,467
European (non-Finnish)	0.000508%	196,672

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.Pro1801Leu
Coding: c.5402C>T
MANE Select: NM_001130987
dbSNP: rs371189093
Type: single nucleotide variant
Location: chr2:71667460 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1801: the c2 7 domain; an α-helix

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

Similar variants

DYSF p.Pro1801= 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+4A>G Pathogenic ★★★ same condition
DYSF c.1276+5G>A Pathogenic ★★★ same condition
DYSF c.1276+5G>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-pro1801leu (accessed [today's date]).

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