Is CAPN12 p.Arg161Cys (c.481C>T) pathogenic?

CAPN12 p.Arg161Cys (c.481C>T) is classified Uncertain significance in CAPN12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely benign (0.1082); Ultra-rare (popmax 0.0472%, sas).

How common is CAPN12 p.Arg161Cys (c.481C>T) in the general population?

CAPN12 p.Arg161Cys (c.481C>T) is ultra-rare (popmax 0.0472%, sas) (gnomAD).

What do computational predictors say about CAPN12 p.Arg161Cys (c.481C>T)?

AlphaMissense predicts likely benign (score 0.1082) — an in-silico prediction, not a clinical call.

CAPN12 p.Arg161Cys

c.481C>T · rs539611909 · VCV2228258

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1082 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0472%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1082	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -10.19	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2	GERP -4, phastCons 0.038
Regional constraint	o/e 1.14	unconstrained · MANE · 13 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	19.92	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 0.0472% South Asian · 43/91,066 alleles

Filtering AF 0.036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0321%

Overall 0.00595% 96/1,614,028 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0472%	2,118
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00424%	23,600
Admixed American	0.00167%	60,022
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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: CAPN12
Protein: p.Arg161Cys
Coding: c.481C>T
MANE Select: NM_144691
dbSNP: rs539611909
Type: single nucleotide variant
Location: chr19:38741856 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 161: the calpain catalytic domain

Full CAPN12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN12 c.1362+80A>G Benign ★★ same type
CAPN12 c.1374+85A>C Benign ★★ same type
CAPN12 c.1583+12G>A Benign ★★ same type
CAPN12 c.1584-39C>T Benign ★★ same type
CAPN12 c.1686+152A>G Benign ★★ same type
CAPN12 c.1745-17C>T Benign ★★ same type
CAPN12 c.1815+25G>A Benign ★★ same type
CAPN12 c.1815+57C>T Benign ★★ 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/capn12-p-arg161cys (accessed [today's date]).

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