Is ITPR2 p.Arg799Cys (c.2395C>T) pathogenic?

ITPR2 p.Arg799Cys (c.2395C>T) is classified Uncertain significance in ITPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: ambiguous (0.5619); Ultra-rare (popmax 0.029%, eas).

How common is ITPR2 p.Arg799Cys (c.2395C>T) in the general population?

ITPR2 p.Arg799Cys (c.2395C>T) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about ITPR2 p.Arg799Cys (c.2395C>T)?

AlphaMissense predicts ambiguous (score 0.5619) — an in-silico prediction, not a clinical call.

ITPR2 p.Arg799Cys

c.2395C>T · VCV3530878

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5619 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Computational evidence

Protein change
AlphaMissense	0.5619	ambiguous
REVEL	0.638	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 61 kb · p 0.0071 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.029% East Asian · 13/44,868 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00173% 28/1,614,106 alleles · ultra-rare exomes 22/1,461,888 · genomes 6/152,218 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,451
South Asian	0.00439%	22,769
Admixed American	0.00167%	60,016
African / African-American	0.00133%	75,010
European (non-Finnish)	0.000763%	131,114

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: ITPR2
Protein: p.Arg799Cys
Coding: c.2395C>T
MANE Select: NM_002223
Type: single nucleotide variant
Location: chr12:26656346 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)

Full ITPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ITPR2 p.Arg799His Uncertain significance ★ same residue
ITPR2 p.Val1162Gly Uncertain significance ★★ same type
ITPR2 c.3801+23G>A Benign ★★ same type
ITPR2 c.5073+10T>A Benign ★★ same type
ITPR2 c.93-10T>A Benign ★★ same type
ITPR2 p.Ala1898Val Benign ★★ same type
ITPR2 p.Arg1180Gln Likely benign ★★ same type
ITPR2 p.Arg1275Gln Likely 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/itpr2-p-arg799cys (accessed [today's date]).

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