Is ITPR1 p.Arg623Ter (c.1867C>T) pathogenic?

ITPR1 p.Arg623Ter (c.1867C>T) is classified Pathogenic in ITPR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-19). Very rare (popmax 8.48e-05%, nfe).

How common is ITPR1 p.Arg623Ter (c.1867C>T) in the general population?

ITPR1 p.Arg623Ter (c.1867C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

ITPR1 p.Arg623Ter

c.1867C>T · rs374124279 · VCV1935236

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 18 of 62
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.89 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP 1.9, phastCons 1
Overall
CADD	46.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,412 alleles

Overall 6.2e-05% 1/1,612,988 alleles · very rare exomes 1/1,460,760 · genomes 0/152,228 · 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.Arg623Ter
Coding: c.1867C>T
MANE Select: NM_001378452
dbSNP: rs374124279
Type: single nucleotide variant
Location: chr3:4667530 (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.Arg623= 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-arg623ter (accessed [today's date]).

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