Is IPMK p.Val133Ala (c.398T>C) pathogenic?

IPMK p.Val133Ala (c.398T>C) is classified Uncertain significance in IPMK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely pathogenic (0.7535); Very rare (popmax 0.000174%, nfe).

How common is IPMK p.Val133Ala (c.398T>C) in the general population?

IPMK p.Val133Ala (c.398T>C) is very rare (popmax 0.000174%, nfe) (gnomAD).

What do computational predictors say about IPMK p.Val133Ala (c.398T>C)?

AlphaMissense predicts likely pathogenic (score 0.7535) — an in-silico prediction, not a clinical call.

IPMK p.Val133Ala

c.398T>C · VCV4276120

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7535 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7535	likely pathogenic
REVEL	0.285	benign-leaning
SaProt	LLR -10.76	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 42 kb · p 3.5e-08 · regional, not allelic
Overall
CADD	23.7	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 0.000174% European (non-Finnish) · 2/1,151,140 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000142% 2/1,409,458 alleles · very rare

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: IPMK
Protein: p.Val133Ala
Coding: c.398T>C
MANE Select: NM_152230
Type: single nucleotide variant
Location: chr10:58216293 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.82 (gnomAD)
Structure: AlphaFold pLDDT 74.50 · 25 PDB
Residue 133: a turn; a binding site

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

Similar variants

IPMK p.Asn124= Benign ★★ same type
IPMK p.Thr32= Benign ★★ same type
IPMK p.Ala228Val Uncertain significance ★ ⚠ same type
IPMK p.Ala250Thr Uncertain significance ★ ⚠ same type
IPMK p.Ala319Val Uncertain significance ★ ⚠ same type
IPMK p.Arg10Gln Uncertain significance ★ ⚠ same type
IPMK p.Arg10Trp Uncertain significance ★ ⚠ same type
IPMK p.Arg320His 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/ipmk-p-val133ala (accessed [today's date]).

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