Is ITPR3 p.Ser1645Phe (c.4934C>T) pathogenic?

ITPR3 p.Ser1645Phe (c.4934C>T) is classified Uncertain significance in ITPR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: ambiguous (0.3809); Ultra-rare (popmax 0.0221%, mid).

How common is ITPR3 p.Ser1645Phe (c.4934C>T) in the general population?

ITPR3 p.Ser1645Phe (c.4934C>T) is ultra-rare (popmax 0.0221%, mid) (gnomAD).

What do computational predictors say about ITPR3 p.Ser1645Phe (c.4934C>T)?

AlphaMissense predicts ambiguous (score 0.3809) — an in-silico prediction, not a clinical call.

ITPR3 p.Ser1645Phe

c.4934C>T · rs547973498 · VCV2230280

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3809 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0221%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3809	ambiguous
REVEL	0.807	moderately pathogenic-leaning
SaProt	LLR -9.22	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -4.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 6,885 bp · p 0.00093 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0221% Middle Eastern · 1/4,520 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000683% 11/1,610,310 alleles · ultra-rare exomes 10/1,458,124 · genomes 1/152,186 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0221%	4,520
Remaining individualsnot grpmax-eligible	0.00161%	62,300
South Asian	0.0011%	90,960
European (non-Finnish)	0.000678%	147,462

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: ITPR3
Protein: p.Ser1645Phe
Coding: c.4934C>T
MANE Select: NM_002224
dbSNP: rs547973498
Type: single nucleotide variant
Location: chr6:33684165 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.04 · 24 PDB
Residue 1645: an α-helix

Full ITPR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ITPR3 p.Thr1424Met Pathogenic/Likely pathogenic ★★ ⚠ same type
ITPR3 p.Ala1352Thr Uncertain significance ★★ ⚠ same type
ITPR3 p.Arg1085Leu Uncertain significance ★★ ⚠ same type
ITPR3 p.Arg2659Cys Uncertain significance ★★ ⚠ same type
ITPR3 p.Asp1968Val Uncertain significance ★★ ⚠ same type
ITPR3 p.Glu669Asp Uncertain significance ★★ ⚠ same type
ITPR3 p.Gly1008Trp Uncertain significance ★★ ⚠ same type
ITPR3 p.Gly2514Glu Uncertain significance ★★ ⚠ 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/itpr3-p-ser1645phe (accessed [today's date]).

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