Is CAPN12 p.Ala409= (c.1227T>G) pathogenic?

CAPN12 p.Ala409= (c.1227T>G) is classified Likely benign in CAPN12 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-02-25). Ultra-rare (popmax 0.0594%, mid); Associated with CAPN12-related disorder.

What condition is associated with CAPN12 p.Ala409= (c.1227T>G)?

CAPN12 p.Ala409= (c.1227T>G) is associated with CAPN12-related disorder (ClinVar).

How common is CAPN12 p.Ala409= (c.1227T>G) in the general population?

CAPN12 p.Ala409= (c.1227T>G) is ultra-rare (popmax 0.0594%, mid) (gnomAD).

CAPN12 p.Ala409=

c.1227T>G · rs1227359941 · VCV3033537

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0594%, mid)

Conditions

CAPN12-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.2	GERP -3.7
Overall
CADD	0.546	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0594% Middle Eastern · 1/1,684 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.0167% 92/551,208 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0594%	1,684
Remaining individualsnot grpmax-eligible	0.0245%	4,088
South Asian	0.0237%	4,217
European (non-Finnish)	0.0174%	5,749
Admixed American	0.0136%	7,340
East Asian	0.00848%	11,796
Ashkenazi Jewishnot grpmax-eligible	0.00843%	11,868
African / African-American	0.00531%	18,824
Finnishnot grpmax-eligible	0.00479%	20,882

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.Ala409=
Coding: c.1227T>G
MANE Select: NM_144691
dbSNP: rs1227359941
Type: single nucleotide variant
Location: chr19:38737291 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 409: the 'domain iii' region; the 'disordered' region

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

Disease context

CAPN12-related disorder

Similar variants

CAPN12 c.1627-6C>A Uncertain significance ★ same condition
CAPN12 p.Gln626Ter Uncertain significance ★ same condition
CAPN12 p.Phe139Val Uncertain significance ★ ⚠ same condition
CAPN12 p.Trp363Arg Uncertain significance ⚠ same condition
CAPN12 c.1583+9C>T Likely benign same condition
CAPN12 c.1879-3C>T Likely benign same condition
CAPN12 c.561-7C>T Likely benign same condition
CAPN12 p.Ala110= Benign same condition

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-ala409 (accessed [today's date]).

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