Is DYSF p.Gln121Pro (c.362A>C) pathogenic?

DYSF p.Gln121Pro (c.362A>C) is classified Uncertain significance in DYSF (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9622); Very rare (popmax 8.72e-05%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2B.

What condition is associated with DYSF p.Gln121Pro (c.362A>C)?

DYSF p.Gln121Pro (c.362A>C) is associated with autosomal recessive limb-girdle muscular dystrophy type 2B (ClinVar).

How common is DYSF p.Gln121Pro (c.362A>C) in the general population?

DYSF p.Gln121Pro (c.362A>C) is very rare (popmax 8.72e-05%, nfe) (gnomAD).

What do computational predictors say about DYSF p.Gln121Pro (c.362A>C)?

AlphaMissense predicts likely pathogenic (score 0.9622) — an in-silico prediction, not a clinical call.

DYSF p.Gln121Pro

Q: How is Dysferlin-related limb-girdle muscular dystrophy R2 inherited?

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

c.362A>C · rs1444283069 · VCV2585024

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9622 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.72e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2B

Computational evidence

Protein change
AlphaMissense	0.9622	likely pathogenic · top 9% in DYSF
REVEL	0.572	indeterminate
SaProt	LLR -13.41	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM Q120P vs ClinVar Q121P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.72e-05% European (non-Finnish) · 1/1,146,540 alleles

Overall 0.000657% 1/152,192 alleles · very rare

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.Gln121Pro
Coding: c.362A>C
MANE Select: NM_001130987
dbSNP: rs1444283069
Type: single nucleotide variant
Location: chr2:71511823 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 121: a β-strand

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

Disease context

autosomal recessive limb-girdle muscular dystrophy type 2B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dysferlin-related limb-girdle muscular dystrophy R2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult
Prevalence: 1-9 / 1 000 000 (United Kingdom)

Similar variants

DYSF p.Gln121Ter 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.1149+4A>G 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-gln121pro (accessed [today's date]).

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