Is ITPR1 p.Leu375= (c.1125G>A) pathogenic?

ITPR1 p.Leu375= (c.1125G>A) is classified Benign in ITPR1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-28). Common (popmax 12.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal dominant cerebellar ataxia.

What condition is associated with ITPR1 p.Leu375= (c.1125G>A)?

ITPR1 p.Leu375= (c.1125G>A) is associated with autosomal dominant cerebellar ataxia (ClinVar).

ITPR1 p.Leu375=

Q: How common is ITPR1 p.Leu375= (c.1125G>A) in the general population?

ITPR1 p.Leu375= (c.1125G>A) is common (popmax 12.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1125G>A · rs2306869 · VCV345605

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 12.9%, afr) — too common for a highly-penetrant pathogenic allele

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 -1.8	GERP -4
Overall
CADD	1.268	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.9% African / African-American · 9,696/74,880 alleles

Filtering AF 12.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.6%

Overall 0.747% 12,040/1,612,258 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.9%	8
Remaining individualsnot grpmax-eligible	1.02%	98
Middle Eastern	0.992%	101
Admixed American	0.991%	101
South Asian	0.396%	252
East Asian	0.283%	353
European (non-Finnish)	0.0472%	2,120
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,955

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.Leu375=
Coding: c.1125G>A
MANE Select: NM_001378452
dbSNP: rs2306869
Type: single nucleotide variant
Location: chr3:4658252 (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-leu375 (accessed [today's date]).

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