Is ITPR1 p.Pro1059Ser (c.3175C>T) pathogenic?

ITPR1 p.Pro1059Ser (c.3175C>T) is classified Conflicting classifications of pathogenicity in ITPR1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-01-08). AlphaMissense: likely benign (0.2278); Very rare (popmax 0.0022%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ITPR1 p.Pro1059Ser (c.3175C>T)?

ITPR1 p.Pro1059Ser (c.3175C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ITPR1 p.Pro1059Ser (c.3175C>T) in the general population?

ITPR1 p.Pro1059Ser (c.3175C>T) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about ITPR1 p.Pro1059Ser (c.3175C>T)?

AlphaMissense predicts likely benign (score 0.2278) — an in-silico prediction, not a clinical call.

ITPR1 p.Pro1059Ser

c.3175C>T · rs771272478 · VCV2154849

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2278 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2278	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.091, phastCons 0.94
Regional constraint	o/e 0.58	unconstrained · MANE · 3,046 bp · p 1e-06 · regional, not allelic
Overall
CADD	22.2	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 0.0022% European (non-Finnish) · 26/1,179,898 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00341% 55/1,613,886 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0844%	1,184
Remaining individualsnot grpmax-eligible	0.0048%	20,822
European (non-Finnish)grpmax	0.0022%	45,381
Admixed American	0.00167%	60,006

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1059Ser
Coding: c.3175C>T
MANE Select: NM_001378452
dbSNP: rs771272478
Type: single nucleotide variant
Location: chr3:4683399 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ITPR1 p.Pro1059Leu Uncertain significance ★ ⚠ same residue
ITPR1 p.Leu605Phe Likely pathogenic ★★ same condition
ITPR1 p.Thr2434Ile Likely pathogenic ★★ same condition
ITPR1 c.1554+4G>A Uncertain significance ★★ same condition
ITPR1 c.3564+5G>T Uncertain significance ★★ same condition
ITPR1 p.Ala1222Thr Uncertain significance ★★ ⚠ same condition
ITPR1 p.Ala1222Val Uncertain significance ★★ same condition
ITPR1 p.Ala1480Thr 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-pro1059ser (accessed [today's date]).

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