Is CAPN3 p.Ala726Val (c.2177C>T) pathogenic?

CAPN3 p.Ala726Val (c.2177C>T) is classified Uncertain significance in CAPN3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-06-30). AlphaMissense: likely benign (0.0967); Very rare (popmax 0.000169%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

What condition is associated with CAPN3 p.Ala726Val (c.2177C>T)?

CAPN3 p.Ala726Val (c.2177C>T) is associated with autosomal recessive limb-girdle muscular dystrophy type 2A, muscular dystrophy, limb-girdle, autosomal dominant 4 (ClinVar).

How common is CAPN3 p.Ala726Val (c.2177C>T) in the general population?

CAPN3 p.Ala726Val (c.2177C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CAPN3 p.Ala726Val (c.2177C>T)?

AlphaMissense predicts likely benign (score 0.0967) — an in-silico prediction, not a clinical call.

CAPN3 p.Ala726Val

Q: How is Calpain-3-related limb-girdle muscular dystrophy R1 inherited?

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

c.2177C>T · rs2141223812 · VCV1210371

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0967 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2A

Computational evidence

Protein change
AlphaMissense	0.0967	likely benign
REVEL	0.449	indeterminate
SaProt	LLR -5.97	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.75	donor gain · deltas
Pangolin	Δ0.53	gain · loss 0.16 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.1	GERP 0.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,948 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,810 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: CAPN3
Protein: p.Ala726Val
Coding: c.2177C>T
MANE Select: NM_000070
dbSNP: rs2141223812
Type: single nucleotide variant
Location: chr15:42410489 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.18 · 5 PDB
Residue 726: the 'domain iv' region; an α-helix; the ef-hand 3 domain

Full CAPN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: muscular dystrophy, limb-girdle, autosomal dominant 4

For Calpain-3-related limb-girdle muscular dystrophy R1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CAPN3 p.Ala726= Likely benign ★ same residue
CAPN3 p.Ala726Ser Uncertain significance ★ ⚠ same residue
CAPN3 c.1115+5G>C Pathogenic ★★★ same condition
CAPN3 c.1194-2A>G Pathogenic ★★★ same condition
CAPN3 c.1194-9A>G Pathogenic ★★★ same condition
CAPN3 c.1746-20C>G Pathogenic ★★★ same condition
CAPN3 c.1993-1G>A Pathogenic ★★★ same condition
CAPN3 c.499-1G>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/capn3-p-ala726val (accessed [today's date]).

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