Is ITPR1 p.Pro434= (c.1302G>A) pathogenic?

ITPR1 p.Pro434= (c.1302G>A) is classified Benign/Likely benign in ITPR1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). Low-frequency (popmax 3.35%, afr); Associated with aniridia-cerebellar ataxia-intellectual disability syndrome.

What condition is associated with ITPR1 p.Pro434= (c.1302G>A)?

ITPR1 p.Pro434= (c.1302G>A) is associated with aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29, spinocerebellar ataxia type 15/16 (ClinVar).

How common is ITPR1 p.Pro434= (c.1302G>A) in the general population?

ITPR1 p.Pro434= (c.1302G>A) is low-frequency (popmax 3.35%, afr) (gnomAD).

ITPR1 p.Pro434=

c.1302G>A · rs34252981 · VCV345641

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.35%, afr)

Conditions

aniridia-cerebellar ataxia-intellectual disability syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -4
Overall
CADD	0.126	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.35% African / African-American · 2,514/75,010 alleles

Filtering AF 3.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.2%

Overall 0.197% 3,173/1,613,674 alleles · low-frequency exomes 1,704/1,461,428 · genomes 1,469/152,246 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.35%	30
Middle Eastern	0.429%	233
Admixed American	0.272%	368
Remaining individualsnot grpmax-eligible	0.261%	383
Ashkenazi Jewishnot grpmax-eligible	0.257%	390
European (non-Finnish)	0.0184%	5,436
South Asian	0.0121%	8,276
East Asian	0.00669%	14,953

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.Pro434=
Coding: c.1302G>A
MANE Select: NM_001378452
dbSNP: rs34252981
Type: single nucleotide variant
Location: chr3:4662132 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 434: the mir 5 domain

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

Disease context

aniridia-cerebellar ataxia-intellectual disability syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spinocerebellar ataxia type 29 spinocerebellar ataxia type 15/16 autosomal dominant cerebellar ataxia

Similar variants

ITPR1 p.Pro434Ala Uncertain significance ★ same residue
ITPR1 p.Arg241Lys Pathogenic/Likely pathogenic ★★ same condition
ITPR1 p.Arg269Trp Pathogenic/Likely pathogenic ★★ same condition
ITPR1 p.Arg504Gly Likely pathogenic ★★ same condition
ITPR1 p.Arg506Trp Likely pathogenic ★★ same condition
ITPR1 p.Arg511Gly Likely pathogenic ★★ same condition
ITPR1 p.Arg511Ser Likely pathogenic ★★ same condition
ITPR1 p.Gly2554Arg Pathogenic/Likely pathogenic ★★ 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-pro434 (accessed [today's date]).

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