Is DYSF p.Leu221Val (c.661C>G) pathogenic?

DYSF p.Leu221Val (c.661C>G) is classified Benign/Likely benign in DYSF (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0713); Common (popmax 7.01%, afr) — too common for a highly-penetrant pathogenic allele; Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

What do computational predictors say about DYSF p.Leu221Val (c.661C>G)?

AlphaMissense predicts likely benign (score 0.0713) — an in-silico prediction, not a clinical call.

DYSF p.Leu221Val

Q: What condition is associated with DYSF p.Leu221Val (c.661C>G)?

DYSF p.Leu221Val (c.661C>G) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin, autosomal recessive limb-girdle muscular dystrophy type 2B (ClinVar).

Q: How common is DYSF p.Leu221Val (c.661C>G) in the general population?

DYSF p.Leu221Val (c.661C>G) is common (popmax 7.01%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.661C>G · rs13407355 · VCV94343

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0713 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.01%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.0713	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.9, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	18.67	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 L189V vs ClinVar L221V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.01% African / African-American · 5,262/75,052 alleles

Filtering AF 6.85% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.79%

Overall 0.445% 7,180/1,614,184 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.01%	14
East Asian	1.94%	52
Remaining individualsnot grpmax-eligible	0.728%	137
Middle Eastern	0.578%	173
Admixed American	0.556%	180
South Asian	0.0362%	2,760
European (non-Finnish)	0.016%	6,243
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Leu221Val
Coding: c.661C>G
MANE Select: NM_001130987
dbSNP: rs13407355
Type: single nucleotide variant
Location: chr2:71513823 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 221: a β-strand; the c2 2 domain

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.Leu221= Likely benign ★ 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
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-leu221val (accessed [today's date]).

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