Is CNN2 p.Ile142Val (c.424A>G) pathogenic?

CNN2 p.Ile142Val (c.424A>G) is classified Uncertain significance in CNN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). AlphaMissense: likely benign (0.0978); Very rare (popmax 0.0011%, sas).

How common is CNN2 p.Ile142Val (c.424A>G) in the general population?

CNN2 p.Ile142Val (c.424A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CNN2 p.Ile142Val (c.424A>G)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

CNN2 p.Ile142Val

c.424A>G · VCV4230827

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -3.42	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 11	GERP 0.93, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 11 kb · p 0.17 · regional, not allelic
Overall
CADD	22.1	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 0.0011% South Asian · 1/90,904 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,612,616 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,904
European (non-Finnish)	0.000254%	393,111

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.Ile142Val
Coding: c.424A>G
MANE Select: NM_004368
Type: single nucleotide variant
Location: chr19:1036163 (GRCh38)
Gene constraint: LOEUF 1.006 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.62 · 1 PDB

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-ile142val (accessed [today's date]).

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