Is CCNA2 p.Val215Met (c.643G>A) pathogenic?

CCNA2 p.Val215Met (c.643G>A) is classified Uncertain significance in CCNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely pathogenic (0.9607); Ultra-rare (popmax 0.0164%, mid).

How common is CCNA2 p.Val215Met (c.643G>A) in the general population?

CCNA2 p.Val215Met (c.643G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CCNA2 p.Val215Met (c.643G>A)?

AlphaMissense predicts likely pathogenic (score 0.9607) — an in-silico prediction, not a clinical call.

CCNA2 p.Val215Met

c.643G>A · VCV4222029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9607 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9607	likely pathogenic
REVEL	0.442	indeterminate
SaProt	LLR -11.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 3,366 bp · p 4.5e-15 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000929% 15/1,613,828 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Finnishnot grpmax-eligible	0.00156%	64,034
South Asian	0.0011%	91,088
European (non-Finnish)	0.00102%	98,318

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: CCNA2
Protein: p.Val215Met
Coding: c.643G>A
MANE Select: NM_001237
Type: single nucleotide variant
Location: chr4:121820693 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.80 · 115 PDB
Residue 215: an α-helix

Full CCNA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EXOSC9 p.Ala438Val Uncertain significance ★★ ⚠ same type
CCN1 c.277+50G>C Benign ★★ same type
CCN1 c.64-124G>A Benign ★★ same type
CCN1 c.-107C>A Benign ★★ same type
CCN1 p.Ser316Cys Likely benign ★★ ⚠ same type
CCN1 p.Tyr300= Benign ★★ same type
CCNA2 c.*828C>G Benign ★★ same type
CCNA2 p.Leu126= 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/ccna2-p-val215met (accessed [today's date]).

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