Is ITPR3 p.Arg2007Trp (c.6019C>T) pathogenic?

ITPR3 p.Arg2007Trp (c.6019C>T) is classified Uncertain significance in ITPR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely pathogenic (0.9316); Ultra-rare (popmax 0.0802%, sas).

How common is ITPR3 p.Arg2007Trp (c.6019C>T) in the general population?

ITPR3 p.Arg2007Trp (c.6019C>T) is ultra-rare (popmax 0.0802%, sas) (gnomAD).

What do computational predictors say about ITPR3 p.Arg2007Trp (c.6019C>T)?

AlphaMissense predicts likely pathogenic (score 0.9316) — an in-silico prediction, not a clinical call.

ITPR3 p.Arg2007Trp

c.6019C>T · VCV3530908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9316 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0802%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9316	likely pathogenic
REVEL	0.813	moderately pathogenic-leaning
SaProt	LLR -14.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP -2.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 6,885 bp · p 0.00093 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0802% South Asian · 73/91,066 alleles

Filtering AF 0.0654% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0599%

Overall 0.00799% 129/1,613,842 alleles · ultra-rare exomes 120/1,461,764 · genomes 9/152,078 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0802%	1,247
Middle Eastern	0.0658%	1,521
Admixed American	0.01%	9,998
African / African-American	0.00935%	10,696
Remaining individualsnot grpmax-eligible	0.0064%	15,620
European (non-Finnish)	0.00297%	33,714

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.Arg2007Trp
Coding: c.6019C>T
MANE Select: NM_002224
Type: single nucleotide variant
Location: chr6:33687048 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.04 · 24 PDB

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

Similar variants

ITPR3 p.Arg2007Pro Uncertain significance ★ ⚠ same residue
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

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-arg2007trp (accessed [today's date]).

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