Is DYSF p.Asp992Asn (c.2974G>A) pathogenic?

DYSF p.Asp992Asn (c.2974G>A) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-30). AlphaMissense: likely benign (0.2906); Ultra-rare (popmax 0.0297%, sas); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Asp992Asn (c.2974G>A) in the general population?

DYSF p.Asp992Asn (c.2974G>A) is ultra-rare (popmax 0.0297%, sas) (gnomAD).

What do computational predictors say about DYSF p.Asp992Asn (c.2974G>A)?

AlphaMissense predicts likely benign (score 0.2906) — an in-silico prediction, not a clinical call.

DYSF p.Asp992Asn

Q: What condition is associated with DYSF p.Asp992Asn (c.2974G>A)?

DYSF p.Asp992Asn (c.2974G>A) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin, autosomal recessive limb-girdle muscular dystrophy type 2B (ClinVar).

c.2974G>A · rs200422222 · VCV1011538

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2906 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0297%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.2906	likely benign
REVEL	0.649	pathogenic-leaning
SaProt	LLR -7.15	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	26.3	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 D974N vs ClinVar D992N) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0297% South Asian · 27/90,982 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.0031% 50/1,613,692 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0297%	3,370
Admixed American	0.00333%	29,994
East Asian	0.00223%	44,896
Remaining individualsnot grpmax-eligible	0.0016%	62,480
Finnishnot grpmax-eligible	0.00156%	63,996
European (non-Finnish)	0.00144%	69,402
African / African-American	0.00133%	74,924

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.Asp992Asn
Coding: c.2974G>A
MANE Select: NM_001130987
dbSNP: rs200422222
Type: single nucleotide variant
Location: chr2:71569929 (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

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2B

Similar variants

DYSF p.Asp992Glu Uncertain significance ★★ ⚠ 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+1G>C Pathogenic ★★★ same condition
DYSF c.1149+4A>G 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-asp992asn (accessed [today's date]).

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