Is CAPN1 p.Arg512Cys (c.1534C>T) pathogenic?

CAPN1 p.Arg512Cys (c.1534C>T) is classified Likely pathogenic in CAPN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-01). AlphaMissense: likely pathogenic (0.9636); Very rare (popmax 0.00333%, amr).

How common is CAPN1 p.Arg512Cys (c.1534C>T) in the general population?

CAPN1 p.Arg512Cys (c.1534C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CAPN1 p.Arg512Cys (c.1534C>T)?

AlphaMissense predicts likely pathogenic (score 0.9636) — an in-silico prediction, not a clinical call.

CAPN1 p.Arg512Cys

c.1534C>T · rs753019478 · VCV871873

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9636	likely pathogenic ✓ concordant with ClinVar
REVEL	0.905	moderately pathogenic-leaning
SaProt	LLR -13.87	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	29.7	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 0.00333% Admixed American · 2/60,000 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,613,264 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,000
Remaining individualsnot grpmax-eligible	0.0016%	62,458
European (non-Finnish)	8.48e-05%	1,179,878

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.Arg512Cys
Coding: c.1534C>T
MANE Select: NM_005186
dbSNP: rs753019478
Type: single nucleotide variant
Location: chr11:65206643 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 512: the 'domain iii' region

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

Similar variants

CAPN1 p.Arg512Leu Uncertain significance ★ ⚠ same residue
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

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-arg512cys (accessed [today's date]).

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