Is CAPN12 p.Cys287Arg (c.859T>C) pathogenic?

CAPN12 p.Cys287Arg (c.859T>C) is classified Benign in CAPN12 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-07-09). AlphaMissense: likely benign (0.0347); Common (popmax 11.8%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CAPN12 p.Cys287Arg (c.859T>C)?

AlphaMissense predicts likely benign (score 0.0347) — an in-silico prediction, not a clinical call.

CAPN12 p.Cys287Arg

Q: How common is CAPN12 p.Cys287Arg (c.859T>C) in the general population?

CAPN12 p.Cys287Arg (c.859T>C) is common (popmax 11.8%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.859T>C · rs12983010 · VCV1242051

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0347 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 11.8%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0347	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -3.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP -2.7, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 13 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	15.55	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 11.8% Admixed American · 7,032/59,764 alleles

Filtering AF 11.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.4%

Overall 7.25% 116,707/1,609,288 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	11.8%	8
African / African-American	11.6%	9
South Asian	10.6%	9
East Asian	8.67%	12
Middle Eastern	7.59%	13
Remaining individualsnot grpmax-eligible	7.52%	13
Ashkenazi Jewishnot grpmax-eligible	7.23%	14
European (non-Finnish)	6.63%	15
Finnishnot grpmax-eligible	3.5%	29
Amishnot grpmax-eligible	0.658%	152

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.Cys287Arg
Coding: c.859T>C
MANE Select: NM_144691
dbSNP: rs12983010
Type: single nucleotide variant
Location: chr19:38738449 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 287: the calpain catalytic domain; a UniProt-annotated variant site (in)

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

Similar variants

CAPN12 p.Cys287Tyr Uncertain significance ★ ⚠ same residue
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

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-cys287arg (accessed [today's date]).

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