Is CAPN1 p.Arg433Pro (c.1298G>C) pathogenic?

CAPN1 p.Arg433Pro (c.1298G>C) is classified Benign/Likely benign in CAPN1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.5671); Common (popmax 16.1%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CAPN1 p.Arg433Pro (c.1298G>C)?

AlphaMissense predicts likely pathogenic (score 0.5671) — an in-silico prediction, not a clinical call.

CAPN1 p.Arg433Pro

Q: How common is CAPN1 p.Arg433Pro (c.1298G>C) in the general population?

CAPN1 p.Arg433Pro (c.1298G>C) is common (popmax 16.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1298G>C · rs10895991 · VCV1253816

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.5671 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 16.1%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5671	likely pathogenic
REVEL	0.63	indeterminate
SaProt	LLR -12.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	31.0	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 16.1% East Asian · 7,208/44,834 alleles

Filtering AF 15.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 15.6%

Overall 7.73% 124,607/1,612,110 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	16.1%	6
Middle Eastern	14.5%	7
Ashkenazi Jewishnot grpmax-eligible	12.3%	8
Remaining individualsnot grpmax-eligible	9.07%	11
European (non-Finnish)	8%	13
Finnishnot grpmax-eligible	6.8%	15
Amishnot grpmax-eligible	6.04%	17
Admixed American	5.27%	19
South Asian	4.38%	23
African / African-American	1.87%	53

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: CAPN1
Protein: p.Arg433Pro
Coding: c.1298G>C
MANE Select: NM_005186
dbSNP: rs10895991
Type: single nucleotide variant
Location: chr11:65204815 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 433: a UniProt-annotated variant site (in); the 'domain iii' region

Full CAPN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN1 c.1605+5G>A Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.267+2T>C Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.338-1G>A Pathogenic ★★ same type
CAPN1 c.759+1G>A Pathogenic ★★ same type
CAPN1 c.843+1G>C Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.929+2T>A Likely pathogenic ★★ same type
CAPN1 p.Arg285Ter Pathogenic/Likely pathogenic ★★ same type
CAPN1 p.Arg385Ter Pathogenic/Likely 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/capn1-p-arg433pro (accessed [today's date]).

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