Is ITPR3 p.Pro1069= (c.3207G>A) pathogenic?

ITPR3 p.Pro1069= (c.3207G>A) is classified Benign in ITPR3 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-05-04). Common (popmax 30.1%, mid) — too common for a highly-penetrant pathogenic allele.

ITPR3 p.Pro1069=

Q: How common is ITPR3 p.Pro1069= (c.3207G>A) in the general population?

ITPR3 p.Pro1069= (c.3207G>A) is common (popmax 30.1%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3207G>A · rs2229637 · VCV1261107

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 30.1%, mid) — too common for a highly-penetrant pathogenic allele

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 -4.3	GERP -4.8
Overall
CADD	4.62	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 30.1% Middle Eastern · 1,822/6,044 alleles

Filtering AF 29% ClinGen BA1/BS1 input FAF95, joint · FAF99 28.9%

Overall 26.4% 425,258/1,609,852 alleles · common exomes 388,729/1,457,640 · genomes 36,529/152,212 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	33.4%	3
Middle Easterngrpmax	30.1%	3
European (non-Finnish)	29%	3
Remaining individualsnot grpmax-eligible	26%	4
Admixed American	22.8%	4
Amishnot grpmax-eligible	22.1%	5
African / African-American	19.5%	5
Finnishnot grpmax-eligible	16.8%	6
South Asian	13.3%	8
East Asian	10%	10

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: ITPR3
Protein: p.Pro1069=
Coding: c.3207G>A
MANE Select: NM_002224
dbSNP: rs2229637
Type: single nucleotide variant
Location: chr6:33675781 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.04 · 24 PDB
Residue 1069: an α-helix

Full ITPR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ITPR3 p.Pro1069Leu Uncertain significance ★ ⚠ same residue
ITPR3 p.Thr1424Met Pathogenic/Likely pathogenic ★★ ⚠ same type
ITPR3 p.Ala1352Thr Uncertain significance ★★ ⚠ same type
ITPR3 p.Arg1085Leu Uncertain significance ★★ ⚠ same type
ITPR3 p.Arg2659Cys Uncertain significance ★★ ⚠ same type
ITPR3 p.Asp1968Val Uncertain significance ★★ ⚠ same type
ITPR3 p.Glu669Asp Uncertain significance ★★ ⚠ same type
ITPR3 p.Gly1008Trp Uncertain significance ★★ ⚠ same type

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/itpr3-p-pro1069 (accessed [today's date]).

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