Is CAPN3 p.Leu712Phe (c.2134C>T) pathogenic?

CAPN3 p.Leu712Phe (c.2134C>T) is classified Likely pathogenic in CAPN3 (ClinVar, Expert panel, 8 submitters; last evaluated 2026-04-29). AlphaMissense: likely pathogenic (0.9001); Very rare (popmax 0.000339%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with CAPN3 p.Leu712Phe (c.2134C>T)?

CAPN3 p.Leu712Phe (c.2134C>T) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive disease, autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Leu712Phe (c.2134C>T) in the general population?

CAPN3 p.Leu712Phe (c.2134C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CAPN3 p.Leu712Phe (c.2134C>T)?

AlphaMissense predicts likely pathogenic (score 0.9001) — an in-silico prediction, not a clinical call.

CAPN3 p.Leu712Phe

c.2134C>T · rs794727318 · VCV195450

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9001 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

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):

PM2_Supporting PP1_Moderate PM3_Strong PP3 PP4

Curation rationale (ClinGen, verbatim)

The NM_000070.3: c.2134C>T variant in CAPN3 is a missense variant predicted to cause the substitution of leucine by phenylalanine at amino acid position 712, p.(Leu712Phe). The variant has been detected in at least six patients with LGMD2A (PMID: 17562833, 26886200, 30919934; GRASP-LGMD Consortium internal data communication), including in a homozygous state without consanguinity in 3 unrelated patients (1.0 pt; PMID: 17562833, 26886200, 30919934). In a fourth patient, the variant was confirmed in trans with a pathogenic CAPN3 variant (c.1981del, p.(Ile661Ter), 1.0 pt) (PMID: 17562833, 26886200, 30919934) (PM3_Strong). At least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness (PP4). This variant was also observed to segregate with autosomal recessive LGMD in three affected family members from one family (PMID: 17562833; PP1_Moderate). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000007757 (4/1180004 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.855, which is above the threshold of 0.70 (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (specifications v2.0.0; 04/29/2026): PM3_Strong, PP4, PP1_Moderate, PM2_Supporting, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.9001	likely pathogenic ✓ concordant with ClinVar
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -13.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,004 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,868 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.Leu712Phe
Coding: c.2134C>T
MANE Select: NM_000070
dbSNP: rs794727318
Type: single nucleotide variant
Location: chr15:42410446 (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 712: the 'domain iv' region; a β-strand; the ef-hand 2 domain

Full CAPN3 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 disease autosomal recessive limb-girdle muscular dystrophy type 2A muscular dystrophy, limb-girdle, autosomal dominant 4

Similar variants

CAPN3 p.Leu712= Likely benign ★ same residue
CAPN3 p.Leu712_Ter822del Likely pathogenic 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-leu712phe (accessed [today's date]).

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