Is DYSF p.Leu1864Pro (c.5591T>C) pathogenic?

DYSF p.Leu1864Pro (c.5591T>C) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.8739); Very rare (popmax 0.00334%, sas); Associated with Inborn genetic diseases.

How common is DYSF p.Leu1864Pro (c.5591T>C) in the general population?

DYSF p.Leu1864Pro (c.5591T>C) is very rare (popmax 0.00334%, sas) (gnomAD).

What do computational predictors say about DYSF p.Leu1864Pro (c.5591T>C)?

AlphaMissense predicts likely pathogenic (score 0.8739) — an in-silico prediction, not a clinical call.

DYSF p.Leu1864Pro

Q: What condition is associated with DYSF p.Leu1864Pro (c.5591T>C)?

DYSF p.Leu1864Pro (c.5591T>C) 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.5591T>C · rs768704227 · VCV854870

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8739 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8739	likely pathogenic
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -13.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 L1825P vs ClinVar L1864P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% South Asian · 3/89,854 alleles

Filtering AF 0.000887% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000446%

Overall 0.000274% 4/1,458,274 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00334%	29,951
European (non-Finnish)	8.48e-05%	1,178,564

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.Leu1864Pro
Coding: c.5591T>C
MANE Select: NM_001130987
dbSNP: rs768704227
Type: single nucleotide variant
Location: chr2:71669156 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1864: the c2 7 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.Leu1864Gln Uncertain significance ★ ⚠ 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-leu1864pro (accessed [today's date]).

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