Is DYSF p.Asp992Glu (c.2976T>A) pathogenic?

DYSF p.Asp992Glu (c.2976T>A) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-21). AlphaMissense: likely pathogenic (0.907); Very rare (popmax 0.0011%, nfe); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Asp992Glu (c.2976T>A) in the general population?

DYSF p.Asp992Glu (c.2976T>A) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about DYSF p.Asp992Glu (c.2976T>A)?

AlphaMissense predicts likely pathogenic (score 0.907) — an in-silico prediction, not a clinical call.

DYSF p.Asp992Glu

Q: What condition is associated with DYSF p.Asp992Glu (c.2976T>A)?

DYSF p.Asp992Glu (c.2976T>A) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.2976T>A · rs1328741092 · VCV1412547

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.907	likely pathogenic
REVEL	0.586	indeterminate
SaProt	LLR -10.77	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.87 · evaluated, not missing
Constraint at this position
Conservation	phyloP -14	GERP -4.3
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	0.044	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 D974E vs ClinVar D992E) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,838 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000889% 13/1,461,528 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.Asp992Glu
Coding: c.2976T>A
MANE Select: NM_001130987
dbSNP: rs1328741092
Type: single nucleotide variant
Location: chr2:71569931 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 992: 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.Asp992Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
DYSF p.Asp992His 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+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-asp992glu (accessed [today's date]).

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