Is CAPN12 p.Arg28Gln (c.83G>A) pathogenic?

CAPN12 p.Arg28Gln (c.83G>A) is classified Conflicting classifications of pathogenicity in CAPN12 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0794); Rare (popmax 0.572%, afr).

How common is CAPN12 p.Arg28Gln (c.83G>A) in the general population?

CAPN12 p.Arg28Gln (c.83G>A) is rare (popmax 0.572%, afr) (gnomAD).

What do computational predictors say about CAPN12 p.Arg28Gln (c.83G>A)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

CAPN12 p.Arg28Gln

c.83G>A · rs112433506 · VCV732600

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.572%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -4.94	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 2.6	GERP 0.23, phastCons 0.99
Regional constraint	o/e 1.14	unconstrained · MANE · 13 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	17.59	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 0.572% African / African-American · 429/75,054 alleles

Filtering AF 0.527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.509%

Overall 0.0315% 508/1,614,212 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.572%	175
Remaining individualsnot grpmax-eligible	0.0592%	1,689
Admixed American	0.0433%	2,309
Middle Eastern	0.0165%	6,062
East Asian	0.00223%	44,882
European (non-Finnish)	0.00119%	84,289

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.Arg28Gln
Coding: c.83G>A
MANE Select: NM_144691
dbSNP: rs112433506
Type: single nucleotide variant
Location: chr19:38744083 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63

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

Similar variants

CAPN12 p.Arg28Trp 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
CAPN12 c.1815+25G>A 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-arg28gln (accessed [today's date]).

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