Is ITPR1 p.Ser22= (c.66G>A) pathogenic?

ITPR1 p.Ser22= (c.66G>A) is classified Benign/Likely benign in ITPR1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.0656%, nfe); Associated with autosomal dominant cerebellar ataxia.

What condition is associated with ITPR1 p.Ser22= (c.66G>A)?

ITPR1 p.Ser22= (c.66G>A) is associated with autosomal dominant cerebellar ataxia (ClinVar).

How common is ITPR1 p.Ser22= (c.66G>A) in the general population?

ITPR1 p.Ser22= (c.66G>A) is ultra-rare (popmax 0.0656%, nfe) (gnomAD).

ITPR1 p.Ser22=

c.66G>A · rs112944532 · VCV345339

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0656%, nfe)

Conditions

autosomal dominant cerebellar ataxia

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 -1	GERP -2.4
Overall
CADD	8.817	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0656% European (non-Finnish) · 771/1,174,936 alleles

Filtering AF 0.0618% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0602%

Overall 0.0534% 856/1,603,558 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0688%	1,454
European (non-Finnish)grpmax	0.0656%	1,524
Remaining individualsnot grpmax-eligible	0.0322%	3,106
Admixed American	0.0239%	4,186
East Asian	0.00677%	14,776
African / African-American	0.00537%	18,610

Finnish 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.Ser22=
Coding: c.66G>A
MANE Select: NM_001378452
dbSNP: rs112944532
Type: single nucleotide variant
Location: chr3:4516557 (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 p.Ser22Leu Uncertain significance ★ ⚠ same residue
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

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-ser22 (accessed [today's date]).

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