Is CAPN13 p.Arg144Pro (c.431G>C) pathogenic?

CAPN13 p.Arg144Pro (c.431G>C) is classified Uncertain significance in CAPN13 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely pathogenic (0.9428); Ultra-rare (popmax 0.0347%, afr).

How common is CAPN13 p.Arg144Pro (c.431G>C) in the general population?

CAPN13 p.Arg144Pro (c.431G>C) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

What do computational predictors say about CAPN13 p.Arg144Pro (c.431G>C)?

AlphaMissense predicts likely pathogenic (score 0.9428) — an in-silico prediction, not a clinical call.

CAPN13 p.Arg144Pro

c.431G>C · rs374775173 · VCV3137079

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9428 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9428	likely pathogenic · top 1% in CAPN13
REVEL	0.258	benign-leaning
SaProt	LLR -12.06	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.33	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 0.097	GERP -2.9, phastCons 0.22
Regional constraint	o/e 1.05	unconstrained · MANE · 57 kb · p 0.12 · regional, not allelic
Overall
CADD	21.6	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 0.0347% African / African-American · 26/74,936 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00173% 28/1,613,874 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,882
European (non-Finnish)	0.00017%	589,939

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: CAPN13
Protein: p.Arg144Pro
Coding: c.431G>C
MANE Select: NM_144575
dbSNP: rs374775173
Type: single nucleotide variant
Location: chr2:30770406 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.25 · 1 PDB
Residue 144: the calpain catalytic domain

Full CAPN13 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN13 p.Arg144Cys Uncertain significance ★ ⚠ same residue
CAPN13 p.Arg144His Uncertain significance ★ ⚠ same residue
CAPN13 p.Ala172Ser Uncertain significance ★ ⚠ same type
CAPN13 p.Ala215Ser Uncertain significance ★ ⚠ same type
CAPN13 p.Ala2Val Uncertain significance ★ ⚠ same type
CAPN13 p.Ala326Val Uncertain significance ★ ⚠ same type
CAPN13 p.Ala460Gly Uncertain significance ★ ⚠ same type
CAPN13 p.Ala510Pro Uncertain significance ★ ⚠ same type

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/capn13-p-arg144pro (accessed [today's date]).

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