Is ITPR1 p.Val1223= (c.3669G>A) pathogenic?

ITPR1 p.Val1223= (c.3669G>A) is classified Benign/Likely benign in ITPR1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-29). Ultra-rare (popmax 0.041%, nfe); Associated with aniridia-cerebellar ataxia-intellectual disability syndrome.

What condition is associated with ITPR1 p.Val1223= (c.3669G>A)?

ITPR1 p.Val1223= (c.3669G>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.Val1223= (c.3669G>A) in the general population?

ITPR1 p.Val1223= (c.3669G>A) is ultra-rare (popmax 0.041%, nfe) (gnomAD).

ITPR1 p.Val1223=

c.3669G>A · rs201263269 · VCV741041

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.041%, nfe)

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 0.35	GERP 1.2, phastCons 0.98
Overall
CADD	6.81	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.041% European (non-Finnish) · 483/1,178,584 alleles

Filtering AF 0.0379% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0367%

Overall 0.0316% 507/1,606,534 alleles · ultra-rare exomes 486/1,454,168 · genomes 21/152,366 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.041%	2,440
Remaining individualsnot grpmax-eligible	0.0112%	8,909
Admixed American	0.0101%	9,935
Finnishnot grpmax-eligible	0.00836%	11,966
African / African-American	0.00666%	15,004
South Asian	0.00111%	89,982

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.Val1223=
Coding: c.3669G>A
MANE Select: NM_001378452
dbSNP: rs201263269
Type: single nucleotide variant
Location: chr3:4685173 (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

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

Similar variants

ITPR1 p.Val1223Met 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-val1223 (accessed [today's date]).

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