Is CAPN3 p.Pro78Thr (c.232C>A) pathogenic?

CAPN3 p.Pro78Thr (c.232C>A) is classified Conflicting classifications of pathogenicity in CAPN3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.101); Rare (popmax 0.214%, mid); Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

What condition is associated with CAPN3 p.Pro78Thr (c.232C>A)?

CAPN3 p.Pro78Thr (c.232C>A) is associated with autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Pro78Thr (c.232C>A) in the general population?

CAPN3 p.Pro78Thr (c.232C>A) is rare (popmax 0.214%, mid) (gnomAD).

What do computational predictors say about CAPN3 p.Pro78Thr (c.232C>A)?

AlphaMissense predicts likely benign (score 0.101) — an in-silico prediction, not a clinical call.

CAPN3 p.Pro78Thr

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.232C>A · rs138867099 · VCV287449

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.101 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.214%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2A

Computational evidence

Protein change
AlphaMissense	0.101	likely benign
REVEL	0.648	pathogenic-leaning
SaProt	LLR -10.03	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	25.0	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 0.214% Middle Eastern · 13/6,062 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.0235% 380/1,614,190 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.294%	340
Middle Easterngrpmax	0.214%	466
Admixed American	0.0816%	1,225
Remaining individualsnot grpmax-eligible	0.0288%	3,473
African / African-American	0.0227%	4,414
European (non-Finnish)	0.0162%	6,178
South Asian	0.00549%	18,217

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro78Thr
Coding: c.232C>A
MANE Select: NM_000070
dbSNP: rs138867099
Type: single nucleotide variant
Location: chr15:42360037 (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 78: the calpain catalytic domain; a β-strand

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

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.Pro78fs Pathogenic/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
CAPN3 p.Ala702Val 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-pro78thr (accessed [today's date]).

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