Is ITPR1 p.Val494Ile (c.1480G>A) pathogenic?

ITPR1 p.Val494Ile (c.1480G>A) is classified Benign/Likely benign in ITPR1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0947); Rare (popmax 0.693%, mid); Associated with autosomal dominant cerebellar ataxia.

What condition is associated with ITPR1 p.Val494Ile (c.1480G>A)?

ITPR1 p.Val494Ile (c.1480G>A) is associated with autosomal dominant cerebellar ataxia (ClinVar).

How common is ITPR1 p.Val494Ile (c.1480G>A) in the general population?

ITPR1 p.Val494Ile (c.1480G>A) is rare (popmax 0.693%, mid) (gnomAD).

What do computational predictors say about ITPR1 p.Val494Ile (c.1480G>A)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

ITPR1 p.Val494Ile

c.1480G>A · rs41289628 · VCV345684

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.693%, mid)

Conditions

autosomal dominant cerebellar ataxia

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.37	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 18 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	24.0	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 0.693% Middle Eastern · 42/6,062 alleles

Filtering AF 0.646% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.628%

Overall 0.49% 7,904/1,613,778 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.966%	104
Middle Easterngrpmax	0.693%	144
South Asian	0.691%	145
European (non-Finnish)	0.53%	189
Remaining individualsnot grpmax-eligible	0.496%	202
Admixed American	0.31%	323
Finnishnot grpmax-eligible	0.216%	464
African / African-American	0.0773%	1,293
East Asian	0.00223%	44,874

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val494Ile
Coding: c.1480G>A
MANE Select: NM_001378452
dbSNP: rs41289628
Type: single nucleotide variant
Location: chr3:4663132 (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

autosomal dominant cerebellar ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ITPR1 c.*1531G>A Uncertain significance ★★ same condition
ITPR1 p.Arg1761Gln Uncertain significance ★★ same condition
ITPR1 p.Arg343Lys Uncertain significance ★★ same condition
ITPR1 p.Asp1959Asn Uncertain significance ★★ same condition
ITPR1 p.Glu2128Val Uncertain significance ★★ ⚠ same condition
ITPR1 p.Gly1782Arg Uncertain significance ★★ same condition
ITPR1 p.Met2750Val Uncertain significance ★★ same condition
ITPR1 p.Ser2180Asn 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-val494ile (accessed [today's date]).

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