Is ITPR2 p.Met679Val (c.2035A>G) pathogenic?

ITPR2 p.Met679Val (c.2035A>G) is classified Uncertain significance in ITPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-25). AlphaMissense: likely benign (0.0527); Very rare (popmax 0.00223%, eas).

How common is ITPR2 p.Met679Val (c.2035A>G) in the general population?

ITPR2 p.Met679Val (c.2035A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ITPR2 p.Met679Val (c.2035A>G)?

AlphaMissense predicts likely benign (score 0.0527) — an in-silico prediction, not a clinical call.

ITPR2 p.Met679Val

c.2035A>G · rs746664465 · VCV3111751

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0527 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0527	likely benign
REVEL	0.227	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	Δ0.40	acceptor loss, 22 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.017	GERP -3, phastCons 0.099
Regional constraint	o/e 0.91	unconstrained · MANE · 61 kb · p 0.0071 · regional, not allelic
Overall
CADD	14.19	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 0.00223% East Asian · 1/44,888 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,982 alleles · very rare exomes 6/1,461,766 · genomes 2/152,216 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,888
European (non-Finnish)	0.000593%	168,572

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.Met679Val
Coding: c.2035A>G
MANE Select: NM_002223
dbSNP: rs746664465
Type: single nucleotide variant
Location: chr12:26657864 (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.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-met679val (accessed [today's date]).

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