Is ITPR1 p.Ser1799Arg (c.5397T>G) pathogenic?

ITPR1 p.Ser1799Arg (c.5397T>G) is classified Uncertain significance in ITPR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-05). AlphaMissense: likely pathogenic (0.957); Ultra-rare (popmax 0.0118%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ITPR1 p.Ser1799Arg (c.5397T>G)?

ITPR1 p.Ser1799Arg (c.5397T>G) is associated with Inborn genetic diseases (ClinVar).

How common is ITPR1 p.Ser1799Arg (c.5397T>G) in the general population?

ITPR1 p.Ser1799Arg (c.5397T>G) is ultra-rare (popmax 0.0118%, nfe) (gnomAD).

What do computational predictors say about ITPR1 p.Ser1799Arg (c.5397T>G)?

AlphaMissense predicts likely pathogenic (score 0.957) — an in-silico prediction, not a clinical call.

ITPR1 p.Ser1799Arg

c.5397T>G · rs376278816 · VCV1335840

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.957 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.957	likely pathogenic
REVEL	0.695	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 1.4	phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 23 kb · p 0.063 · regional, not allelic
Overall
CADD	21.2	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 0.0118% European (non-Finnish) · 139/1,179,860 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00956%

Overall 0.00917% 148/1,613,806 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0118%	8,488
Remaining individualsnot grpmax-eligible	0.00961%	10,411
African / African-American	0.00401%	24,965

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.Ser1799Arg
Coding: c.5397T>G
MANE Select: NM_001378452
dbSNP: rs376278816
Type: single nucleotide variant
Location: chr3:4735207 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ITPR1 p.Ser1799Ile Uncertain significance ★ ⚠ same residue
ITPR1 p.Ser1799Asn Uncertain significance ★ same residue
ITPR1 p.Leu605Phe Likely pathogenic ★★ same condition
ITPR1 p.Thr2434Ile Likely pathogenic ★★ same condition
ITPR1 c.1554+4G>A Uncertain significance ★★ same condition
ITPR1 c.3564+5G>T Uncertain significance ★★ same condition
ITPR1 p.Ala1222Thr Uncertain significance ★★ ⚠ same condition
ITPR1 p.Ala1222Val Uncertain significance ★★ same condition

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-ser1799arg (accessed [today's date]).

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