Is ITPKB p.Pro44Ser (c.130C>T) pathogenic?

ITPKB p.Pro44Ser (c.130C>T) is classified Uncertain significance in ITPKB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-17). AlphaMissense: likely benign (0.1284); Very rare (popmax 0.00289%, nfe).

How common is ITPKB p.Pro44Ser (c.130C>T) in the general population?

ITPKB p.Pro44Ser (c.130C>T) is very rare (popmax 0.00289%, nfe) (gnomAD).

What do computational predictors say about ITPKB p.Pro44Ser (c.130C>T)?

AlphaMissense predicts likely benign (score 0.1284) — an in-silico prediction, not a clinical call.

ITPKB p.Pro44Ser

c.130C>T · rs1484533620 · VCV2513432

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1284 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00289%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1284	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP 1.3, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 1,929 bp · p 2.3e-06 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00289% European (non-Finnish) · 34/1,176,676 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00225% 36/1,597,368 alleles · very rare exomes 34/1,445,236 · genomes 2/152,132 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00289%	34,608
Remaining individualsnot grpmax-eligible	0.00162%	61,914
African / African-American	0.00134%	74,664

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: ITPKB
Protein: p.Pro44Ser
Coding: c.130C>T
MANE Select: NM_002221
dbSNP: rs1484533620
Type: single nucleotide variant
Location: chr1:226737329 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.58
Residue 44: the 'disordered' region

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

Similar variants

ITPKB p.Glu906Gln Uncertain significance ★★ ⚠ same type
ITPKB p.Pro358Ser Uncertain significance ★★ ⚠ same type
ITPKB p.Pro415His Uncertain significance ★★ ⚠ same type
ITPKB p.Thr757Ala Uncertain significance ★★ ⚠ same type
ITPKB c.-8C>T Benign ★★ same type
ITPKB p.Ala632= Benign ★★ same type
ITPKB p.Asn592= Benign ★★ same type
ITPKB p.Asp320Ala Benign/Likely benign ★★ 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/itpkb-p-pro44ser (accessed [today's date]).

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