Is ITPR1 p.Arg784Cys (c.2350C>T) pathogenic?

ITPR1 p.Arg784Cys (c.2350C>T) is classified Uncertain significance in ITPR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely pathogenic (0.6484); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with ITPR1 p.Arg784Cys (c.2350C>T)?

ITPR1 p.Arg784Cys (c.2350C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ITPR1 p.Arg784Cys (c.2350C>T) in the general population?

ITPR1 p.Arg784Cys (c.2350C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ITPR1 p.Arg784Cys (c.2350C>T)?

AlphaMissense predicts likely pathogenic (score 0.6484) — an in-silico prediction, not a clinical call.

ITPR1 p.Arg784Cys

c.2350C>T · VCV4622344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6484 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6484	likely pathogenic
REVEL	0.852	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 18 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	33.0	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,878 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000806% 13/1,613,856 alleles · very rare exomes 11/1,461,684 · genomes 2/152,172 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,878
African / African-American	0.00133%	74,932
European (non-Finnish)	0.000932%	107,261

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.Arg784Cys
Coding: c.2350C>T
MANE Select: NM_001378452
Type: single nucleotide variant
Location: chr3:4673281 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ITPR1 p.Arg784His Uncertain significance ★★ ⚠ same residue
ITPR1 p.Leu605Phe Likely pathogenic ★★ same condition
ITPR1 p.Thr2434Ile Likely pathogenic ★★ same condition
ITPR1 c.1554+4G>A Uncertain significance ★★ same condition
ITPR1 c.3564+5G>T Uncertain significance ★★ same condition
ITPR1 p.Ala1222Thr Uncertain significance ★★ ⚠ same condition
ITPR1 p.Ala1222Val Uncertain significance ★★ same condition
ITPR1 p.Ala1480Thr Uncertain significance ★★ same condition

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-arg784cys (accessed [today's date]).

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