Is CAPN12 p.Thr334Ala (c.1000A>G) pathogenic?

CAPN12 p.Thr334Ala (c.1000A>G) is classified Benign in CAPN12 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-07-05). AlphaMissense: likely benign (0.1509); Common (popmax 32.2%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CAPN12 p.Thr334Ala (c.1000A>G)?

AlphaMissense predicts likely benign (score 0.1509) — an in-silico prediction, not a clinical call.

CAPN12 p.Thr334Ala

Q: How common is CAPN12 p.Thr334Ala (c.1000A>G) in the general population?

CAPN12 p.Thr334Ala (c.1000A>G) is common (popmax 32.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1000A>G · rs73038948 · VCV1293793

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1509 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 32.2%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1509	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.1, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 13 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	23.0	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 32.2% Middle Eastern · 1,947/6,044 alleles

Filtering AF 31% ClinGen BA1/BS1 input FAF95, joint · FAF99 30.5%

Overall 16.9% 271,625/1,608,948 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	35.4%	3
Middle Easterngrpmax	32.2%	3
Ashkenazi Jewishnot grpmax-eligible	21.6%	5
European (non-Finnish)	18.2%	5
Remaining individualsnot grpmax-eligible	16.7%	6
South Asian	16.1%	6
Finnishnot grpmax-eligible	16%	6
Admixed American	12.4%	8
African / African-American	8.27%	12
East Asian	0.297%	336

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr334Ala
Coding: c.1000A>G
MANE Select: NM_144691
dbSNP: rs73038948
Type: single nucleotide variant
Location: chr19:38737604 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 334: 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-thr334ala (accessed [today's date]).

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