Is ITPR1 p.Arg376Ser (c.1126C>A) pathogenic?

ITPR1 p.Arg376Ser (c.1126C>A) is classified Uncertain significance in ITPR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-26). AlphaMissense: likely pathogenic (0.8431); Very rare (popmax 8.48e-05%, nfe).

How common is ITPR1 p.Arg376Ser (c.1126C>A) in the general population?

ITPR1 p.Arg376Ser (c.1126C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ITPR1 p.Arg376Ser (c.1126C>A)?

AlphaMissense predicts likely pathogenic (score 0.8431) — an in-silico prediction, not a clinical call.

ITPR1 p.Arg376Ser

c.1126C>A · VCV3360286

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8431 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.8431	likely pathogenic
REVEL	0.443	indeterminate
SaProt	—	withheld · numbering disagrees past residue 334 · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,220 bp · p 0.088 · regional, not allelic
Overall
CADD	23.7	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 8.48e-05% European (non-Finnish) · 1/1,178,736 alleles

Overall 6.2e-05% 1/1,612,106 alleles · very rare exomes 0/1,459,998 · genomes 1/152,108 · joint denominator

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.Arg376Ser
Coding: c.1126C>A
MANE Select: NM_001378452
Type: single nucleotide variant
Location: chr3:4658253 (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.Arg376Cys Uncertain significance ★ same residue
ITPR1 p.Arg376His Uncertain significance ★ same residue
ITPR1 p.Arg376Leu Uncertain significance ★ same residue
ITPR1 p.Arg376Pro 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

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-arg376ser (accessed [today's date]).

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