Is CCNA2 p.Ile409Val (c.1225A>G) pathogenic?

CCNA2 p.Ile409Val (c.1225A>G) is classified Uncertain significance in CCNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.0724); Ultra-rare (popmax 0.012%, afr).

How common is CCNA2 p.Ile409Val (c.1225A>G) in the general population?

CCNA2 p.Ile409Val (c.1225A>G) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about CCNA2 p.Ile409Val (c.1225A>G)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

CCNA2 p.Ile409Val

c.1225A>G · VCV4222025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.46	donor gain · deltas
Constraint at this position
Conservation	phyloP 2.9	GERP 2, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 3,366 bp · p 4.5e-15 · regional, not allelic
Overall
CADD	21.9	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 0.012% African / African-American · 9/75,026 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.00322% 52/1,613,706 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,336
Remaining individualsnot grpmax-eligible	0.008%	12,498
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,588
European (non-Finnish)	0.00297%	33,709
East Asian	0.00223%	44,878
Admixed American	0.00167%	59,910

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.Ile409Val
Coding: c.1225A>G
MANE Select: NM_001237
Type: single nucleotide variant
Location: chr4:121818069 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.80 · 115 PDB
Residue 409: 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-ile409val (accessed [today's date]).

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