Is DYSF p.Phe876Ile (c.2626T>A) pathogenic?

DYSF p.Phe876Ile (c.2626T>A) is classified Uncertain significance in DYSF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: ambiguous (0.5028); Very rare (popmax 6.84e-05%); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Phe876Ile (c.2626T>A) in the general population?

DYSF p.Phe876Ile (c.2626T>A) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about DYSF p.Phe876Ile (c.2626T>A)?

AlphaMissense predicts ambiguous (score 0.5028) — an in-silico prediction, not a clinical call.

DYSF p.Phe876Ile

Q: What condition is associated with DYSF p.Phe876Ile (c.2626T>A)?

DYSF p.Phe876Ile (c.2626T>A) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.2626T>A · VCV4806182

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5028 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.5028	ambiguous
REVEL	0.363	indeterminate
SaProt	LLR -6.33	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.046, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 18 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	23.7	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 F858I vs ClinVar F876I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,870 alleles · very rare

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.Phe876Ile
Coding: c.2626T>A
MANE Select: NM_001130987
Type: single nucleotide variant
Location: chr2:71568011 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 876: a β-strand

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.Phe876fs Pathogenic/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+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-phe876ile (accessed [today's date]).

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