Is ITPKB p.Pro461Ser (c.1381C>T) pathogenic?

ITPKB p.Pro461Ser (c.1381C>T) is classified Likely benign in ITPKB (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-29). AlphaMissense: likely benign (0.0957); Rare (popmax 0.656%, nfe).

How common is ITPKB p.Pro461Ser (c.1381C>T) in the general population?

ITPKB p.Pro461Ser (c.1381C>T) is rare (popmax 0.656%, nfe) (gnomAD).

What do computational predictors say about ITPKB p.Pro461Ser (c.1381C>T)?

AlphaMissense predicts likely benign (score 0.0957) — an in-silico prediction, not a clinical call.

ITPKB p.Pro461Ser

c.1381C>T · VCV4689081

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0957 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.656%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0957	likely benign
REVEL	0.01	strongly benign-leaning
SaProt	LLR -6.88	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 1.8	GERP -1.2, phastCons 0.024
Regional constraint	o/e 1.16	unconstrained · MANE · 1,929 bp · p 2.3e-06 · regional, not allelic
Overall
CADD	5.002	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 0.656% European (non-Finnish) · 7,739/1,179,434 alleles

Filtering AF 0.644% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.639%

Overall 0.553% 8,909/1,612,240 alleles · rare exomes 8,308/1,459,930 · genomes 601/152,310 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.656%	152
Finnishnot grpmax-eligible	0.624%	160
Remaining individualsnot grpmax-eligible	0.477%	210
Admixed American	0.407%	246
Middle Eastern	0.396%	252
South Asian	0.132%	758
African / African-American	0.105%	950
Ashkenazi Jewishnot grpmax-eligible	0.0407%	2,459

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.Pro461Ser
Coding: c.1381C>T
MANE Select: NM_002221
Type: single nucleotide variant
Location: chr1:226736078 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.58
Residue 461: 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-pro461ser (accessed [today's date]).

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