Is CAPN12 p.Arg480Pro (c.1439G>C) pathogenic?

CAPN12 p.Arg480Pro (c.1439G>C) is classified Uncertain significance in CAPN12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-09). AlphaMissense: ambiguous (0.4618); Very rare (popmax 0.00136%, sas).

How common is CAPN12 p.Arg480Pro (c.1439G>C) in the general population?

CAPN12 p.Arg480Pro (c.1439G>C) is very rare (popmax 0.00136%, sas) (gnomAD).

What do computational predictors say about CAPN12 p.Arg480Pro (c.1439G>C)?

AlphaMissense predicts ambiguous (score 0.4618) — an in-silico prediction, not a clinical call.

CAPN12 p.Arg480Pro

c.1439G>C · VCV3263172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4618 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, sas)

Computational evidence

Protein change
AlphaMissense	0.4618	ambiguous
REVEL	0.419	indeterminate
SaProt	LLR -11.24	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 13 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	23.7	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 0.00136% South Asian · 1/73,692 alleles

Overall 6.81e-05% 1/1,469,098 alleles · very rare exomes 1/1,318,066 · genomes 0/151,032 · joint denominator

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.Arg480Pro
Coding: c.1439G>C
MANE Select: NM_144691
Type: single nucleotide variant
Location: chr19:38736254 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 480: the 'domain iii' region

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

Similar variants

CAPN12 p.Arg480Cys Uncertain significance ★ ⚠ same residue
CAPN12 p.Arg480Leu 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

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-arg480pro (accessed [today's date]).

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