Is CAPN13 p.Pro423Thr (c.1267C>A) pathogenic?

CAPN13 p.Pro423Thr (c.1267C>A) is classified Uncertain significance in CAPN13 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-12). AlphaMissense: likely benign (0.1428); Very rare (popmax 6.84e-05%).

How common is CAPN13 p.Pro423Thr (c.1267C>A) in the general population?

CAPN13 p.Pro423Thr (c.1267C>A) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about CAPN13 p.Pro423Thr (c.1267C>A)?

AlphaMissense predicts likely benign (score 0.1428) — an in-silico prediction, not a clinical call.

CAPN13 p.Pro423Thr

c.1267C>A · rs1457836604 · VCV3137065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1428 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1428	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -6.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.49	acceptor loss · deltas
Pangolin	Δ0.40	gain · loss 0.28 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 9.2	GERP 2.3, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 57 kb · p 0.12 · regional, not allelic
Overall
CADD	21.1	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 6.84e-05%

Overall 6.84e-05% 1/1,461,684 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: CAPN13
Protein: p.Pro423Thr
Coding: c.1267C>A
MANE Select: NM_144575
dbSNP: rs1457836604
Type: single nucleotide variant
Location: chr2:30743561 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.25 · 1 PDB

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

Similar variants

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
CAPN13 p.Ala564Val Uncertain significance ★ ⚠ same type
CAPN13 p.Ala90Ser 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-pro423thr (accessed [today's date]).

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