Is ITPR2 p.Arg344His (c.1031G>A) pathogenic?

ITPR2 p.Arg344His (c.1031G>A) is classified Uncertain significance in ITPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely benign (0.0922); Ultra-rare (popmax 0.0872%, sas).

How common is ITPR2 p.Arg344His (c.1031G>A) in the general population?

ITPR2 p.Arg344His (c.1031G>A) is ultra-rare (popmax 0.0872%, sas) (gnomAD).

What do computational predictors say about ITPR2 p.Arg344His (c.1031G>A)?

AlphaMissense predicts likely benign (score 0.0922) — an in-silico prediction, not a clinical call.

ITPR2 p.Arg344His

c.1031G>A · rs377464722 · VCV2391967

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0922 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0872%, sas)

Computational evidence

Protein change
AlphaMissense	0.0922	likely benign
REVEL	0.335	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 1.6, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 175 kb · p 1.6e-22 · regional, not allelic
Overall
CADD	22.0	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 0.0872% South Asian · 79/90,576 alleles

Filtering AF 0.0717% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.066%

Overall 0.0123% 198/1,610,272 alleles · ultra-rare exomes 175/1,458,118 · genomes 23/152,154 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0872%	1,147
Admixed American	0.0453%	2,210
Middle Eastern	0.0329%	3,036
African / African-American	0.0107%	9,339
European (non-Finnish)	0.00662%	15,102
Remaining individualsnot grpmax-eligible	0.00642%	15,574

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.Arg344His
Coding: c.1031G>A
MANE Select: NM_002223
dbSNP: rs377464722
Type: single nucleotide variant
Location: chr12:26686598 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Residue 344: the mir 4 domain

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

Similar variants

ITPR2 p.Arg344Ser 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-arg344his (accessed [today's date]).

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