Is CAPN12 p.His469Arg (c.1406A>G) pathogenic?

CAPN12 p.His469Arg (c.1406A>G) is classified Benign in CAPN12 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-07-09). AlphaMissense: likely benign (0.0419); Common (popmax 10.1%, sas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CAPN12 p.His469Arg (c.1406A>G)?

AlphaMissense predicts likely benign (score 0.0419) — an in-silico prediction, not a clinical call.

CAPN12 p.His469Arg

Q: How common is CAPN12 p.His469Arg (c.1406A>G) in the general population?

CAPN12 p.His469Arg (c.1406A>G) is common (popmax 10.1%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1406A>G · rs62120074 · VCV1267731

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0419 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.1%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0419	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -4.55	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 4.4	GERP -1.1, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 13 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	14.71	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 10.1% South Asian · 6,911/68,468 alleles

Filtering AF 9.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.81%

Overall 6.49% 93,793/1,444,352 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	10.1%	10
Middle Eastern	7.29%	14
Admixed American	6.86%	15
European (non-Finnish)	6.56%	15
Remaining individualsnot grpmax-eligible	6.55%	15
Ashkenazi Jewishnot grpmax-eligible	6.2%	16
African / African-American	5.08%	20
East Asian	4.72%	21
Finnishnot grpmax-eligible	2.94%	34
Amishnot grpmax-eligible	0.662%	151

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.His469Arg
Coding: c.1406A>G
MANE Select: NM_144691
dbSNP: rs62120074
Type: single nucleotide variant
Location: chr19:38736287 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 469: the 'domain iii' region

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

Similar variants

CAPN12 p.His469Pro Uncertain significance ★ ⚠ same residue
CAPN12 p.His469Tyr Benign ⚠ 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

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-his469arg (accessed [today's date]).

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