Is CNN2 p.Val72Ile (c.214G>A) pathogenic?

CNN2 p.Val72Ile (c.214G>A) is classified Uncertain significance in CNN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.0926); Ultra-rare (popmax 0.04%, afr).

How common is CNN2 p.Val72Ile (c.214G>A) in the general population?

CNN2 p.Val72Ile (c.214G>A) is ultra-rare (popmax 0.04%, afr) (gnomAD).

What do computational predictors say about CNN2 p.Val72Ile (c.214G>A)?

AlphaMissense predicts likely benign (score 0.0926) — an in-silico prediction, not a clinical call.

CNN2 p.Val72Ile

c.214G>A · VCV3494400

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0926 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0926	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -8.87	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 0.17	GERP -2.1, phastCons 0.001
Regional constraint	o/e 0.93	unconstrained · MANE · 11 kb · p 0.17 · regional, not allelic
Overall
CADD	15.69	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% African / African-American · 30/75,010 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00316% 51/1,613,598 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.04%	2,500
Remaining individualsnot grpmax-eligible	0.0288%	3,472
European (non-Finnish)	0.000254%	393,328

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: CNN2
Protein: p.Val72Ile
Coding: c.214G>A
MANE Select: NM_004368
Type: single nucleotide variant
Location: chr19:1032420 (GRCh38)
Gene constraint: LOEUF 1.006 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.62 · 1 PDB
Residue 72: the calponin-homology (ch) domain

Full CNN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNN2 p.Ala126Ser Uncertain significance ★ ⚠ same type
CNN2 p.Ala126Thr Uncertain significance ★ ⚠ same type
CNN2 p.Ala161Thr Uncertain significance ★ ⚠ same type
CNN2 p.Arg227Trp Uncertain significance ★ ⚠ same type
CNN2 p.Arg266Gly Uncertain significance ★ ⚠ same type
CNN2 p.Arg35Cys Uncertain significance ★ ⚠ same type
CNN2 p.Arg35His Uncertain significance ★ ⚠ same type
CNN2 p.Arg77His 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/cnn2-p-val72ile (accessed [today's date]).

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