Is CAPN2 p.Gly72Asp (c.215G>A) pathogenic?

CAPN2 p.Gly72Asp (c.215G>A) is classified Uncertain significance in CAPN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-12). AlphaMissense: likely benign (0.2251); Ultra-rare (popmax 0.0117%, amr).

How common is CAPN2 p.Gly72Asp (c.215G>A) in the general population?

CAPN2 p.Gly72Asp (c.215G>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about CAPN2 p.Gly72Asp (c.215G>A)?

AlphaMissense predicts likely benign (score 0.2251) — an in-silico prediction, not a clinical call.

CAPN2 p.Gly72Asp

c.215G>A · rs756560847 · VCV2399220

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2251 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2251	likely benign
REVEL	0.742	pathogenic-leaning
SaProt	LLR -9.12	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 62 kb · p 0.00029 · regional, not allelic
Overall
CADD	28.9	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 0.0117% Admixed American · 6/51,492 alleles

Filtering AF 0.00507% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00344%

Overall 0.00349% 54/1,548,286 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,582
European (non-Finnish)	0.004%	24,995
Remaining individualsnot grpmax-eligible	0.00167%	59,912
African / African-American	0.00141%	70,920

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: CAPN2
Protein: p.Gly72Asp
Coding: c.215G>A
MANE Select: NM_001748
dbSNP: rs756560847
Type: single nucleotide variant
Location: chr1:223712855 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 3 PDB
Residue 72: the calpain catalytic domain

Full CAPN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN2 p.Ala248Thr Uncertain significance ★★ ⚠ same type
CAPN2 p.Asp48= Benign ★★ same type
CAPN2 p.Lys677Gln Benign ★★ ⚠ same type
CAPN2 p.Ala101Pro Uncertain significance ★ ⚠ same type
CAPN2 p.Ala171Asp Uncertain significance ★ ⚠ same type
CAPN2 p.Ala194Ser Uncertain significance ★ ⚠ same type
CAPN2 p.Ala247Pro Uncertain significance ★ ⚠ same type
CAPN2 p.Ala371Thr Uncertain significance ★ ⚠ 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/capn2-p-gly72asp (accessed [today's date]).

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