Is CAPN3 p.Ser423Pro (c.1267T>C) pathogenic?

CAPN3 p.Ser423Pro (c.1267T>C) is classified Uncertain significance in CAPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-09). AlphaMissense: likely benign (0.328); Absent from gnomAD v4.1.

How common is CAPN3 p.Ser423Pro (c.1267T>C) in the general population?

CAPN3 p.Ser423Pro (c.1267T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPN3 p.Ser423Pro (c.1267T>C)?

AlphaMissense predicts likely benign (score 0.328) — an in-silico prediction, not a clinical call.

CAPN3 p.Ser423Pro

c.1267T>C · rs1555421851 · VCV498273

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.328 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.328	likely benign
REVEL	0.728	pathogenic-leaning
SaProt	LLR -7.69	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	24.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CAPN3
Protein: p.Ser423Pro
Coding: c.1267T>C
MANE Select: NM_000070
dbSNP: rs1555421851
Type: single nucleotide variant
Location: chr15:42399565 (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 423: the 'domain iii' region

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

Similar variants

CAPN3 p.Ser423= Likely benign ★ same residue
CAPN3 c.1115+5G>C Pathogenic ★★★ same type
CAPN3 c.1194-2A>G Pathogenic ★★★ same type
CAPN3 c.1194-9A>G Pathogenic ★★★ same type
CAPN3 c.1746-20C>G Pathogenic ★★★ same type
CAPN3 c.1993-1G>A Pathogenic ★★★ same type
CAPN3 c.499-1G>A Pathogenic ★★★ same type
CAPN3 p.Ala702Val Pathogenic ★★★ 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/capn3-p-ser423pro (accessed [today's date]).

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