Is CAPN2 p.Ile73Phe (c.217A>T) pathogenic?

CAPN2 p.Ile73Phe (c.217A>T) is classified Uncertain significance in CAPN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-03). AlphaMissense: ambiguous (0.4143); Ultra-rare (popmax 0.0175%, amr).

How common is CAPN2 p.Ile73Phe (c.217A>T) in the general population?

CAPN2 p.Ile73Phe (c.217A>T) is ultra-rare (popmax 0.0175%, amr) (gnomAD).

What do computational predictors say about CAPN2 p.Ile73Phe (c.217A>T)?

AlphaMissense predicts ambiguous (score 0.4143) — an in-silico prediction, not a clinical call.

CAPN2 p.Ile73Phe

c.217A>T · VCV3827263

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4143 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4143	ambiguous
REVEL	0.145	moderately benign-leaning
SaProt	LLR -13.57	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -1.4, phastCons 0.9
Regional constraint	o/e 0.88	unconstrained · MANE · 62 kb · p 0.00029 · regional, not allelic
Overall
CADD	22.1	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 0.0175% Admixed American · 9/51,296 alleles

Filtering AF 0.00912% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00675%

Overall 0.000582% 9/1,546,510 alleles · ultra-rare

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.Ile73Phe
Coding: c.217A>T
MANE Select: NM_001748
Type: single nucleotide variant
Location: chr1:223712857 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 3 PDB
Residue 73: 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.Gly72Asp 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

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-ile73phe (accessed [today's date]).

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