Is ITPR1 p.Arg709Cys (c.2125C>T) pathogenic?

ITPR1 p.Arg709Cys (c.2125C>T) is classified Uncertain significance in ITPR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-08). AlphaMissense: likely benign (0.1441); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with ITPR1 p.Arg709Cys (c.2125C>T)?

ITPR1 p.Arg709Cys (c.2125C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ITPR1 p.Arg709Cys (c.2125C>T) in the general population?

ITPR1 p.Arg709Cys (c.2125C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about ITPR1 p.Arg709Cys (c.2125C>T)?

AlphaMissense predicts likely benign (score 0.1441) — an in-silico prediction, not a clinical call.

ITPR1 p.Arg709Cys

c.2125C>T · rs1169304800 · VCV1308975

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1441 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1441	likely benign
REVEL	0.612	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 18 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	26.5	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 0.00534% African / African-American · 4/74,838 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00341% 55/1,610,626 alleles · very rare exomes 53/1,458,594 · genomes 2/152,032 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,709
Admixed American	0.00504%	19,855
Remaining individualsnot grpmax-eligible	0.00481%	20,788
European (non-Finnish)	0.00365%	27,407
East Asian	0.00223%	44,782
South Asian	0.00111%	90,230

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.Arg709Cys
Coding: c.2125C>T
MANE Select: NM_001378452
dbSNP: rs1169304800
Type: single nucleotide variant
Location: chr3:4670847 (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.Arg709His 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-arg709cys (accessed [today's date]).

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