Is ITPR2 p.His2001Leu (c.6002A>T) pathogenic?

ITPR2 p.His2001Leu (c.6002A>T) is classified Uncertain significance in ITPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: likely benign (0.2194); Very rare (popmax 0.00167%, amr).

How common is ITPR2 p.His2001Leu (c.6002A>T) in the general population?

ITPR2 p.His2001Leu (c.6002A>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ITPR2 p.His2001Leu (c.6002A>T)?

AlphaMissense predicts likely benign (score 0.2194) — an in-silico prediction, not a clinical call.

ITPR2 p.His2001Leu

c.6002A>T · VCV3530894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2194 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.2194	likely benign
REVEL	0.496	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 169 kb · p 7.4e-06 · regional, not allelic
Overall
CADD	25.6	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 0.00167% Admixed American · 1/60,012 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000372% 6/1,613,730 alleles · very rare exomes 5/1,461,502 · genomes 1/152,228 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,012
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.000339%	294,922

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.His2001Leu
Coding: c.6002A>T
MANE Select: NM_002223
Type: single nucleotide variant
Location: chr12:26483708 (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-his2001leu (accessed [today's date]).

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