Is DYSF p.Asp643Asn (c.1927G>A) pathogenic?

DYSF p.Asp643Asn (c.1927G>A) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-28). AlphaMissense: likely pathogenic (0.8465); Ultra-rare (popmax 0.013%, nfe); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Asp643Asn (c.1927G>A) in the general population?

DYSF p.Asp643Asn (c.1927G>A) is ultra-rare (popmax 0.013%, nfe) (gnomAD).

What do computational predictors say about DYSF p.Asp643Asn (c.1927G>A)?

AlphaMissense predicts likely pathogenic (score 0.8465) — an in-silico prediction, not a clinical call.

DYSF p.Asp643Asn

Q: What condition is associated with DYSF p.Asp643Asn (c.1927G>A)?

DYSF p.Asp643Asn (c.1927G>A) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.1927G>A · rs121908960 · VCV2023880

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8465 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.013%, nfe)

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	0.8465	likely pathogenic
REVEL	0.586	indeterminate
SaProt	LLR -7.46	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 18 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	27.2	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 D625N vs ClinVar D643N) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.013% European (non-Finnish) · 153/1,180,030 alleles

Filtering AF 0.0113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00998% 161/1,613,964 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.013%	7,713
Remaining individualsnot grpmax-eligible	0.0048%	20,830
Finnishnot grpmax-eligible	0.00469%	21,307
East Asian	0.00223%	44,892
Admixed American	0.00167%	60,006

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.Asp643Asn
Coding: c.1927G>A
MANE Select: NM_001130987
dbSNP: rs121908960
Type: single nucleotide variant
Location: chr2:71553131 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB

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.Asp643Tyr 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-asp643asn (accessed [today's date]).

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