Is ITPR1 p.Pro2747Ser (c.8239C>T) pathogenic?

ITPR1 p.Pro2747Ser (c.8239C>T) is classified Uncertain significance in ITPR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-19). AlphaMissense: likely benign (0.1655); Ultra-rare (popmax 0.0469%, amr).

How common is ITPR1 p.Pro2747Ser (c.8239C>T) in the general population?

ITPR1 p.Pro2747Ser (c.8239C>T) is ultra-rare (popmax 0.0469%, amr) (gnomAD).

What do computational predictors say about ITPR1 p.Pro2747Ser (c.8239C>T)?

AlphaMissense predicts likely benign (score 0.1655) — an in-silico prediction, not a clinical call.

ITPR1 p.Pro2747Ser

c.8239C>T · rs201306619 · VCV1807470

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1655 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0469%, amr)

Computational evidence

Protein change
AlphaMissense	0.1655	likely benign
REVEL	0.425	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 9,366 bp · p 0.96 · regional, not allelic
Overall
CADD	23.5	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 0.0469% Admixed American · 25/53,342 alleles

Filtering AF 0.0325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0278%

Overall 0.00472% 74/1,568,932 alleles · ultra-rare exomes 49/1,416,732 · genomes 25/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0469%	2,134
Ashkenazi Jewishnot grpmax-eligible	0.0243%	4,108
Remaining individualsnot grpmax-eligible	0.00657%	15,219
European (non-Finnish)	0.00329%	30,418

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.Pro2747Ser
Coding: c.8239C>T
MANE Select: NM_001378452
dbSNP: rs201306619
Type: single nucleotide variant
Location: chr3:4846187 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 2747: the 'disordered' region

Full ITPR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ITPR1 c.1252-1G>C Pathogenic/Likely pathogenic ★★ same type
ITPR1 c.1252-1G>T Pathogenic/Likely pathogenic ★★ same type
ITPR1 p.Arg241Lys Pathogenic/Likely pathogenic ★★ same type
ITPR1 p.Arg269Leu Pathogenic/Likely pathogenic ★★ same type
ITPR1 p.Arg269Trp Pathogenic/Likely pathogenic ★★ same type
ITPR1 p.Arg504Gly Likely pathogenic ★★ same type
ITPR1 p.Arg506Trp Likely pathogenic ★★ same type
ITPR1 p.Arg511Gly Likely pathogenic ★★ 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/itpr1-p-pro2747ser (accessed [today's date]).

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