Is ITPR3 p.Ile2245Phe (c.6733A>T) pathogenic?

ITPR3 p.Ile2245Phe (c.6733A>T) is classified Uncertain significance in ITPR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-09). AlphaMissense: likely benign (0.0895); Ultra-rare (popmax 0.0119%, nfe).

How common is ITPR3 p.Ile2245Phe (c.6733A>T) in the general population?

ITPR3 p.Ile2245Phe (c.6733A>T) is ultra-rare (popmax 0.0119%, nfe) (gnomAD).

What do computational predictors say about ITPR3 p.Ile2245Phe (c.6733A>T)?

AlphaMissense predicts likely benign (score 0.0895) — an in-silico prediction, not a clinical call.

ITPR3 p.Ile2245Phe

c.6733A>T · VCV3530918

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0895 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0895	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -6.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 3.4	GERP 0.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 8,233 bp · p 6.2e-16 · regional, not allelic
Overall
CADD	20.6	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0119% European (non-Finnish) · 140/1,180,000 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00964%

Overall 0.009% 145/1,611,606 alleles · ultra-rare exomes 138/1,459,546 · genomes 7/152,060 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0119%	8,429
Remaining individualsnot grpmax-eligible	0.0048%	20,825
African / African-American	0.00267%	37,433

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: ITPR3
Protein: p.Ile2245Phe
Coding: c.6733A>T
MANE Select: NM_002224
Type: single nucleotide variant
Location: chr6:33689276 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.04 · 24 PDB
Residue 2245: an α-helix

Full ITPR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ITPR3 p.Thr1424Met Pathogenic/Likely pathogenic ★★ ⚠ same type
ITPR3 p.Ala1352Thr Uncertain significance ★★ ⚠ same type
ITPR3 p.Arg1085Leu Uncertain significance ★★ ⚠ same type
ITPR3 p.Arg2659Cys Uncertain significance ★★ ⚠ same type
ITPR3 p.Asp1968Val Uncertain significance ★★ ⚠ same type
ITPR3 p.Glu669Asp Uncertain significance ★★ ⚠ same type
ITPR3 p.Gly1008Trp Uncertain significance ★★ ⚠ same type
ITPR3 p.Gly2514Glu Uncertain significance ★★ ⚠ 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/itpr3-p-ile2245phe (accessed [today's date]).

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