Is ITPR3 p.Val1071Phe (c.3211G>T) pathogenic?

ITPR3 p.Val1071Phe (c.3211G>T) is classified Uncertain significance in ITPR3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.8425); Ultra-rare (popmax 0.0444%, nfe).

How common is ITPR3 p.Val1071Phe (c.3211G>T) in the general population?

ITPR3 p.Val1071Phe (c.3211G>T) is ultra-rare (popmax 0.0444%, nfe) (gnomAD).

What do computational predictors say about ITPR3 p.Val1071Phe (c.3211G>T)?

AlphaMissense predicts likely pathogenic (score 0.8425) — an in-silico prediction, not a clinical call.

ITPR3 p.Val1071Phe

c.3211G>T · rs150416587 · VCV2277648

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8425 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0444%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8425	likely pathogenic
REVEL	0.61	indeterminate
SaProt	LLR -9.71	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 14 kb · p 5e-11 · regional, not allelic
Overall
CADD	24.8	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 0.0444% European (non-Finnish) · 523/1,178,604 alleles

Filtering AF 0.0412% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0399%

Overall 0.0345% 555/1,610,316 alleles · ultra-rare exomes 532/1,457,954 · genomes 23/152,362 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0444%	2,254
Remaining individualsnot grpmax-eligible	0.0273%	3,666
Admixed American	0.0168%	5,963
African / African-American	0.00667%	14,996

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.Val1071Phe
Coding: c.3211G>T
MANE Select: NM_002224
dbSNP: rs150416587
Type: single nucleotide variant
Location: chr6:33675785 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.04 · 24 PDB
Residue 1071: 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-val1071phe (accessed [today's date]).

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