Is DYSF p.Glu421Gln (c.1261G>C) pathogenic?

DYSF p.Glu421Gln (c.1261G>C) is classified Pathogenic in DYSF (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-23). AlphaMissense: likely pathogenic (0.7985); Absent from gnomAD v4.1; Associated with Miyoshi muscular dystrophy 1.

What condition is associated with DYSF p.Glu421Gln (c.1261G>C)?

DYSF p.Glu421Gln (c.1261G>C) is associated with Miyoshi muscular dystrophy 1 (ClinVar).

How common is DYSF p.Glu421Gln (c.1261G>C) in the general population?

DYSF p.Glu421Gln (c.1261G>C) is absent from gnomAD v4.1 (gnomAD).

How is Miyoshi myopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DYSF p.Glu421Gln (c.1261G>C)?

AlphaMissense predicts likely pathogenic (score 0.7985) — an in-silico prediction, not a clinical call.

DYSF p.Glu421Gln

c.1261G>C · rs778673716 · VCV2674969

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7985 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Miyoshi muscular dystrophy 1

Computational evidence

Protein change
AlphaMissense	0.7985	likely pathogenic ✓ concordant with ClinVar
REVEL	0.567	indeterminate
SaProt	LLR -10.68	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	25.8	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 E389Q vs ClinVar E421Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DYSF
Protein: p.Glu421Gln
Coding: c.1261G>C
MANE Select: NM_001130987
dbSNP: rs778673716
Type: single nucleotide variant
Location: chr2:71526331 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 421: a β-strand; the c2 3 domain

Full DYSF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Miyoshi muscular dystrophy 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Miyoshi myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult
Prevalence: 1-9 / 1 000 000 (Japan)

Similar variants

DYSF p.Glu421Lys Likely pathogenic ★★★ same residue
DYSF p.Glu421Ter Pathogenic ★ same residue
DYSF c.1033+1G>A Pathogenic ★★★ same condition
DYSF c.1149+1G>A Pathogenic ★★★ same condition
DYSF c.1149+1G>C Pathogenic ★★★ same condition
DYSF c.1276+5G>A Pathogenic ★★★ same condition
DYSF c.1276+5G>C Pathogenic ★★★ same condition
DYSF c.1481-1G>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-glu421gln (accessed [today's date]).

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