Is CIP2A p.Arg508His (c.1523G>A) pathogenic?

CIP2A p.Arg508His (c.1523G>A) is classified Uncertain significance in CIP2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-06). AlphaMissense: likely benign (0.1734); Ultra-rare (popmax 0.0287%, sas).

How common is CIP2A p.Arg508His (c.1523G>A) in the general population?

CIP2A p.Arg508His (c.1523G>A) is ultra-rare (popmax 0.0287%, sas) (gnomAD).

What do computational predictors say about CIP2A p.Arg508His (c.1523G>A)?

AlphaMissense predicts likely benign (score 0.1734) — an in-silico prediction, not a clinical call.

CIP2A p.Arg508His

c.1523G>A · VCV3833546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1734 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0287%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1734	likely benign
REVEL	0.514	indeterminate
SaProt	LLR -9.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	loss · gain 0.02 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 38 kb · p 0.12 · regional, not allelic
Overall
CADD	29.6	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 0.0287% South Asian · 26/90,712 alleles

Filtering AF 0.02% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00643% 103/1,600,664 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0287%	3,489
European (non-Finnish)	0.00599%	16,690
Remaining individualsnot grpmax-eligible	0.00484%	20,669
East Asian	0.00447%	22,370
African / African-American	0.00268%	37,335

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.Arg508His
Coding: c.1523G>A
MANE Select: NM_020890
Type: single nucleotide variant
Location: chr3:108563237 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.09 · 1 PDB
Residue 508: 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-arg508his (accessed [today's date]).

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