Is CIP2A p.Phe500Val (c.1498T>G) pathogenic?

CIP2A p.Phe500Val (c.1498T>G) is classified Uncertain significance in CIP2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-10). AlphaMissense: ambiguous (0.3432); Very rare (popmax 0.00135%, afr).

How common is CIP2A p.Phe500Val (c.1498T>G) in the general population?

CIP2A p.Phe500Val (c.1498T>G) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about CIP2A p.Phe500Val (c.1498T>G)?

AlphaMissense predicts ambiguous (score 0.3432) — an in-silico prediction, not a clinical call.

CIP2A p.Phe500Val

c.1498T>G · VCV3833550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3432 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Computational evidence

Protein change
AlphaMissense	0.3432	ambiguous
REVEL	0.379	indeterminate
SaProt	LLR -7.89	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 38 kb · p 0.12 · regional, not allelic
Overall
CADD	25.6	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 0.00135% African / African-American · 1/73,908 alleles

Overall 0.00014% 2/1,430,728 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	73,908
European (non-Finnish)	8.63e-05%	1,158,374

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: CIP2A
Protein: p.Phe500Val
Coding: c.1498T>G
MANE Select: NM_020890
Type: single nucleotide variant
Location: chr3:108565372 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.09 · 1 PDB
Residue 500: the 'required for homodimerization' region; an α-helix

Full CIP2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CIP2A p.Asp353= Likely benign ★★ same type
CIP2A p.His314Arg Benign ★★ same type
CIP2A p.Ser213Phe Benign ★★ same type
CIP2A p.Ala268Val Uncertain significance ★ ⚠ same type
CIP2A p.Ala26Gly Uncertain significance ★ ⚠ same type
CIP2A p.Ala362Thr Uncertain significance ★ ⚠ same type
CIP2A p.Ala535Thr Uncertain significance ★ ⚠ same type
CIP2A p.Ala695Val 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/cip2a-p-phe500val (accessed [today's date]).

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