Is ITPR2 p.Met941Val (c.2821A>G) pathogenic?

ITPR2 p.Met941Val (c.2821A>G) is classified Uncertain significance in ITPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-17). AlphaMissense: likely benign (0.0498); Ultra-rare (popmax 0.0407%, sas).

How common is ITPR2 p.Met941Val (c.2821A>G) in the general population?

ITPR2 p.Met941Val (c.2821A>G) is ultra-rare (popmax 0.0407%, sas) (gnomAD).

What do computational predictors say about ITPR2 p.Met941Val (c.2821A>G)?

AlphaMissense predicts likely benign (score 0.0498) — an in-silico prediction, not a clinical call.

ITPR2 p.Met941Val

c.2821A>G · VCV4088777

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0498 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0407%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0498	likely benign
REVEL	0.27	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP -3.5, phastCons 0.098
Regional constraint	o/e 0.91	unconstrained · MANE · 61 kb · p 0.0071 · regional, not allelic
Overall
CADD	6.553	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0407% South Asian · 37/90,992 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0267%

Overall 0.00353% 57/1,613,666 alleles · ultra-rare exomes 54/1,461,476 · genomes 3/152,190 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0407%	2,459
Remaining individualsnot grpmax-eligible	0.0176%	5,682
East Asian	0.00892%	11,214
European (non-Finnish)	0.000424%	235,963

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.Met941Val
Coding: c.2821A>G
MANE Select: NM_002223
Type: single nucleotide variant
Location: chr12:26631979 (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.Met941Ile 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-met941val (accessed [today's date]).

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