Is ITPR1 p.Val498Phe (c.1492G>T) pathogenic?

ITPR1 p.Val498Phe (c.1492G>T) is classified Uncertain significance in ITPR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-16). AlphaMissense: likely benign (0.1321); Ultra-rare (popmax 0.015%, amr).

How common is ITPR1 p.Val498Phe (c.1492G>T) in the general population?

ITPR1 p.Val498Phe (c.1492G>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about ITPR1 p.Val498Phe (c.1492G>T)?

AlphaMissense predicts likely benign (score 0.1321) — an in-silico prediction, not a clinical call.

ITPR1 p.Val498Phe

c.1492G>T · rs756745652 · VCV1254280

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1321 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1321	likely benign
REVEL	0.741	pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; 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 10	GERP -0.46, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 18 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	24.0	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 0.015% Admixed American · 9/59,990 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00155% 25/1,613,690 alleles · ultra-rare exomes 22/1,461,596 · genomes 3/152,094 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,666
East Asian	0.00891%	11,220
African / African-American	0.00267%	37,440
South Asian	0.0022%	45,539
European (non-Finnish)	0.000678%	147,474

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.Val498Phe
Coding: c.1492G>T
MANE Select: NM_001378452
dbSNP: rs756745652
Type: single nucleotide variant
Location: chr3:4663144 (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.Val498Ile Uncertain significance ★ same residue
ITPR1 p.Val498= 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-val498phe (accessed [today's date]).

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