Is CAPN12 p.Pro504Leu (c.1511C>T) pathogenic?

CAPN12 p.Pro504Leu (c.1511C>T) is classified Uncertain significance in CAPN12 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-14). AlphaMissense: likely pathogenic (0.7065); Very rare (popmax 0.00866%, afr).

How common is CAPN12 p.Pro504Leu (c.1511C>T) in the general population?

CAPN12 p.Pro504Leu (c.1511C>T) is very rare (popmax 0.00866%, afr) (gnomAD).

What do computational predictors say about CAPN12 p.Pro504Leu (c.1511C>T)?

AlphaMissense predicts likely pathogenic (score 0.7065) — an in-silico prediction, not a clinical call.

CAPN12 p.Pro504Leu

c.1511C>T · rs573400086 · VCV2455355

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7065 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00866%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7065	likely pathogenic
REVEL	0.793	moderately pathogenic-leaning
SaProt	LLR -9.36	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 13 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	23.8	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 0.00866% African / African-American · 6/69,290 alleles

Filtering AF 0.0037% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00254%

Overall 0.000859% 13/1,512,976 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00866%	11,548
Admixed American	0.00824%	12,134
Remaining individualsnot grpmax-eligible	0.0017%	58,666
South Asian	0.00123%	81,106
European (non-Finnish)	8.81e-05%	1,134,890

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.Pro504Leu
Coding: c.1511C>T
MANE Select: NM_144691
dbSNP: rs573400086
Type: single nucleotide variant
Location: chr19:38736182 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 504: the 'domain iii' region

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-pro504leu (accessed [today's date]).

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