Is ITPR1 p.Ile172Thr (c.515T>C) pathogenic?

ITPR1 p.Ile172Thr (c.515T>C) is classified Uncertain significance in ITPR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-21). AlphaMissense: likely benign (0.1478); Very rare (popmax 0.00907%, eas).

How common is ITPR1 p.Ile172Thr (c.515T>C) in the general population?

ITPR1 p.Ile172Thr (c.515T>C) is very rare (popmax 0.00907%, eas) (gnomAD).

What do computational predictors say about ITPR1 p.Ile172Thr (c.515T>C)?

AlphaMissense predicts likely benign (score 0.1478) — an in-silico prediction, not a clinical call.

ITPR1 p.Ile172Thr

c.515T>C · rs146177759 · VCV1807472

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1478 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00907%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1478	likely benign
REVEL	0.593	indeterminate
SaProt	LLR -4.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.95, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 129 kb · p 1.8e-14 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00907% East Asian · 4/44,078 alleles

Filtering AF 0.00302% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.0021% 33/1,571,748 alleles · very rare exomes 29/1,419,420 · genomes 4/152,328 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00907%	11,020
South Asian	0.00477%	20,982
Remaining individualsnot grpmax-eligible	0.00331%	30,243
Admixed American	0.00193%	51,804
European (non-Finnish)	0.00172%	58,073
Finnishnot grpmax-eligible	0.00159%	63,010
African / African-American	0.00137%	72,902

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.Ile172Thr
Coding: c.515T>C
MANE Select: NM_001378452
dbSNP: rs146177759
Type: single nucleotide variant
Location: chr3:4642241 (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

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-ile172thr (accessed [today's date]).

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