Is ITPR1 p.Arg1997His (c.5990G>A) pathogenic?

ITPR1 p.Arg1997His (c.5990G>A) is classified Uncertain significance in ITPR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-19). AlphaMissense: likely pathogenic (0.9202); Ultra-rare (popmax 0.0164%, mid).

How common is ITPR1 p.Arg1997His (c.5990G>A) in the general population?

ITPR1 p.Arg1997His (c.5990G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ITPR1 p.Arg1997His (c.5990G>A)?

AlphaMissense predicts likely pathogenic (score 0.9202) — an in-silico prediction, not a clinical call.

ITPR1 p.Arg1997His

c.5990G>A · rs762758498 · VCV2430877

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9202 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.9202	likely pathogenic
REVEL	0.949	strongly pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 11 kb · p 1.4e-11 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000806% 13/1,613,662 alleles · ultra-rare exomes 10/1,461,522 · genomes 3/152,140 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00401%	24,965
Admixed American	0.00167%	59,992
Remaining individualsnot grpmax-eligible	0.0016%	62,458
South Asian	0.0011%	91,078
European (non-Finnish)	0.000509%	196,622

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.Arg1997His
Coding: c.5990G>A
MANE Select: NM_001378452
dbSNP: rs762758498
Type: single nucleotide variant
Location: chr3:4775252 (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 p.Arg1997Cys Uncertain significance ★★ ⚠ same residue
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

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-arg1997his (accessed [today's date]).

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