Is ITPR1 p.Phe2218Leu (c.6652T>C) pathogenic?

ITPR1 p.Phe2218Leu (c.6652T>C) is classified Uncertain significance in ITPR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-19). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with ITPR1-related disorder.

What condition is associated with ITPR1 p.Phe2218Leu (c.6652T>C)?

ITPR1 p.Phe2218Leu (c.6652T>C) is associated with ITPR1-related disorder (ClinVar).

How common is ITPR1 p.Phe2218Leu (c.6652T>C) in the general population?

ITPR1 p.Phe2218Leu (c.6652T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ITPR1 p.Phe2218Leu (c.6652T>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

ITPR1 p.Phe2218Leu

c.6652T>C · VCV4292263

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

ITPR1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 2% in ITPR1
REVEL	0.857	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 2.8, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 12 kb · p 3.9e-10 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ITPR1
Protein: p.Phe2218Leu
Coding: c.6652T>C
MANE Select: NM_001378452
Type: single nucleotide variant
Location: chr3:4787983 (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

ITPR1-related disorder

Similar variants

ITPR1 c.1252-1G>C Pathogenic/Likely pathogenic ★★ same condition
ITPR1 p.Glu2109Lys Pathogenic/Likely pathogenic ★★ same condition
ITPR1 p.Gly2554Arg Pathogenic/Likely pathogenic ★★ same condition
ITPR1 p.Ile2598Thr Pathogenic/Likely pathogenic ★★ same condition
ITPR1 p.Val1445Met Likely pathogenic ★★ same condition
ITPR1 p.Arg1216Trp Uncertain significance ★★ ⚠ same condition
ITPR1 p.Asp231Val Uncertain significance ★★ ⚠ same condition
ITPR1 p.Glu1055Lys 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-phe2218leu (accessed [today's date]).

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