Is ITPR2 p.Val233Leu (c.697G>T) pathogenic?

ITPR2 p.Val233Leu (c.697G>T) is classified Uncertain significance in ITPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: ambiguous (0.4595); Very rare (popmax 8.58e-05%, nfe).

How common is ITPR2 p.Val233Leu (c.697G>T) in the general population?

ITPR2 p.Val233Leu (c.697G>T) is very rare (popmax 8.58e-05%, nfe) (gnomAD).

What do computational predictors say about ITPR2 p.Val233Leu (c.697G>T)?

AlphaMissense predicts ambiguous (score 0.4595) — an in-silico prediction, not a clinical call.

ITPR2 p.Val233Leu

c.697G>T · VCV4088783

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4595 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.58e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4595	ambiguous
REVEL	0.586	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.39, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 175 kb · p 1.6e-22 · regional, not allelic
Overall
CADD	24.4	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 8.58e-05% European (non-Finnish) · 1/1,165,432 alleles

Overall 6.92e-05% 1/1,444,880 alleles · very rare

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.Val233Leu
Coding: c.697G>T
MANE Select: NM_002223
Type: single nucleotide variant
Location: chr12:26715763 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Residue 233: the mir 3 domain

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

Similar variants

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
ITPR2 p.Asn461= 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-val233leu (accessed [today's date]).

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