Is DYSF p.Glu421Lys (c.1261G>A) pathogenic?

DYSF p.Glu421Lys (c.1261G>A) is classified Likely pathogenic in DYSF (ClinVar, Expert panel, 8 submitters; last evaluated 2026-02-18). AlphaMissense: likely pathogenic (0.9153); Very rare (popmax 0.00447%, eas); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Glu421Lys (c.1261G>A) in the general population?

DYSF p.Glu421Lys (c.1261G>A) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about DYSF p.Glu421Lys (c.1261G>A)?

AlphaMissense predicts likely pathogenic (score 0.9153) — an in-silico prediction, not a clinical call.

DYSF p.Glu421Lys

Q: What condition is associated with DYSF p.Glu421Lys (c.1261G>A)?

DYSF p.Glu421Lys (c.1261G>A) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.1261G>A · rs778673716 · VCV869485

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9153 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

Likely Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):

PM3_Supporting PM2_Supporting PP4_Strong

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.1165G>A variant in the DYSF gene is a missense variant which results in the substitution of glutamic acid to lysine at codon 389, p.(Glu389Lys). This variant is also known as NM_001130987.2: c.1261G>A p.(Glu421Lys). This variant has been identified in at least two individuals with clinical features consistent with limb-girdle muscular dystrophy (PMID: 27647186, 33613410, 34559919; LOVD DYSF_001156), including in unconfirmed phase with a pathogenic variant in one patient (NM_003494.4: c.4003G>A p.(Glu1335Lys) 0.5 pts, PMID: 33613410) (PM3_Supporting). At least one individual with this variant and a second presumed diagnostic DYSF variant exhibited progressive proximal muscle weakness and severely reduced dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 27647186; LOVD Individual #00305668) (PP4_Strong). The Grpmax variant allele frequency in gnomAD v4.1.0 is 0.00004465 (2/44788 East Asian chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The REVEL score for this variant is 0.488 (PP3 and BP4 not met). In summary, this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP guidelines as specified by the ClinGen LGMD VCEP (version 2.0.0; 02/18/2026): PM3_Supporting, PP4_Strong, PM2_Supporting.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9153	likely pathogenic ✓ concordant with ClinVar
REVEL	0.488	indeterminate
SaProt	LLR -13.59	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	27.6	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 E389K vs ClinVar E421K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00447% East Asian · 2/44,788 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.00031% 5/1,611,840 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,394
European (non-Finnish)	0.000255%	392,913

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.Glu421Lys
Coding: c.1261G>A
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

autosomal recessive limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2B neuromuscular disease caused by qualitative or quantitative defects of dysferlin Miyoshi muscular dystrophy 1

Similar variants

DYSF p.Glu421Gln Pathogenic ★ same residue
DYSF p.Glu421Ter Pathogenic ★ same residue
DYSF p.Glu421fs 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.1033+5G>A Likely pathogenic ★★★ same condition
DYSF c.1149+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-glu421lys (accessed [today's date]).

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