Is ITPR1 p.Val414Met (c.1240G>A) pathogenic?

ITPR1 p.Val414Met (c.1240G>A) is classified Uncertain significance in ITPR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-12). AlphaMissense: likely pathogenic (0.8788); Very rare (popmax 0.00268%, afr).

How common is ITPR1 p.Val414Met (c.1240G>A) in the general population?

ITPR1 p.Val414Met (c.1240G>A) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about ITPR1 p.Val414Met (c.1240G>A)?

AlphaMissense predicts likely pathogenic (score 0.8788) — an in-silico prediction, not a clinical call.

ITPR1 p.Val414Met

c.1240G>A · rs1462970629 · VCV1302702

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8788 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.8788	likely pathogenic
REVEL	0.701	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 8.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,220 bp · p 0.088 · regional, not allelic
Overall
CADD	31.0	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 0.00268% African / African-American · 2/74,584 alleles

Filtering AF 0.000445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000188% 3/1,598,244 alleles · very rare exomes 1/1,446,084 · genomes 2/152,160 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,292
European (non-Finnish)	8.58e-05%	1,165,782

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.Val414Met
Coding: c.1240G>A
MANE Select: NM_001378452
dbSNP: rs1462970629
Type: single nucleotide variant
Location: chr3:4661076 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 414: the mir 5 domain

Full ITPR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ITPR1 p.Val414Leu Uncertain significance ★ same residue
ITPR1 p.Val414= Likely benign ★ 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

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-val414met (accessed [today's date]).

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