Is ITPR3 p.Asp44His (c.130G>C) pathogenic?

ITPR3 p.Asp44His (c.130G>C) is classified Uncertain significance in ITPR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-26). AlphaMissense: likely pathogenic (0.852); Ultra-rare (popmax 0.0347%, afr).

How common is ITPR3 p.Asp44His (c.130G>C) in the general population?

ITPR3 p.Asp44His (c.130G>C) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

What do computational predictors say about ITPR3 p.Asp44His (c.130G>C)?

AlphaMissense predicts likely pathogenic (score 0.852) — an in-silico prediction, not a clinical call.

ITPR3 p.Asp44His

c.130G>C · rs146942977 · VCV2397918

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.852 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.852	likely pathogenic
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 15 kb · p 0.28 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0347% African / African-American · 26/75,000 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00167% 27/1,613,630 alleles · ultra-rare exomes 15/1,461,380 · genomes 12/152,250 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,885
Remaining individualsnot grpmax-eligible	0.0016%	62,472

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.Asp44His
Coding: c.130G>C
MANE Select: NM_002224
dbSNP: rs146942977
Type: single nucleotide variant
Location: chr6:33640524 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.04 · 24 PDB

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

Similar variants

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
ITPR3 p.Gly2514Glu 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-asp44his (accessed [today's date]).

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