Is ITPR1 p.Arg293Trp (c.877C>T) pathogenic?

ITPR1 p.Arg293Trp (c.877C>T) is classified Uncertain significance in ITPR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-05). AlphaMissense: likely pathogenic (0.8954); Very rare (popmax 0.00223%, eas).

How common is ITPR1 p.Arg293Trp (c.877C>T) in the general population?

ITPR1 p.Arg293Trp (c.877C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ITPR1 p.Arg293Trp (c.877C>T)?

AlphaMissense predicts likely pathogenic (score 0.8954) — an in-silico prediction, not a clinical call.

ITPR1 p.Arg293Trp

c.877C>T · VCV3720427

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8954	likely pathogenic
REVEL	0.797	moderately pathogenic-leaning
SaProt	LLR -10.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 8,160 bp · p 0.00011 · 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 0.00223% East Asian · 1/44,830 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 10/1,612,492 alleles · very rare exomes 10/1,460,166 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,830
European (non-Finnish)	0.000763%	131,041

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: ITPR1
Protein: p.Arg293Trp
Coding: c.877C>T
MANE Select: NM_001378452
Type: single nucleotide variant
Location: chr3:4652144 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)

Full ITPR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ITPR1 p.Arg293Gln Uncertain significance ★★ ⚠ same residue
ITPR1 c.1252-1G>C Pathogenic/Likely pathogenic ★★ same type
ITPR1 c.1252-1G>T Pathogenic/Likely pathogenic ★★ same type
ITPR1 p.Arg241Lys Pathogenic/Likely pathogenic ★★ same type
ITPR1 p.Arg269Leu Pathogenic/Likely pathogenic ★★ same type
ITPR1 p.Arg269Trp Pathogenic/Likely pathogenic ★★ same type
ITPR1 p.Arg504Gly Likely pathogenic ★★ same type
ITPR1 p.Arg506Trp Likely pathogenic ★★ 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/itpr1-p-arg293trp (accessed [today's date]).

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