Is PI4KB p.Met754Arg (c.2261T>G) pathogenic?

PI4KB p.Met754Arg (c.2261T>G) is classified Pathogenic in PI4KB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-03-13). AlphaMissense: likely pathogenic (0.9962); Absent from gnomAD v4.1; Associated with hearing loss, autosomal dominant 87.

What condition is associated with PI4KB p.Met754Arg (c.2261T>G)?

PI4KB p.Met754Arg (c.2261T>G) is associated with hearing loss, autosomal dominant 87 (ClinVar).

How common is PI4KB p.Met754Arg (c.2261T>G) in the general population?

PI4KB p.Met754Arg (c.2261T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PI4KB p.Met754Arg (c.2261T>G)?

AlphaMissense predicts likely pathogenic (score 0.9962) — an in-silico prediction, not a clinical call.

PI4KB p.Met754Arg

c.2261T>G · rs2528612732 · VCV2443953

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9962 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hearing loss, autosomal dominant 87

Computational evidence

Protein change
AlphaMissense	0.9962	likely pathogenic ✓ concordant with ClinVar
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -16.67	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Constraint at this position
Conservation	phyloP 9.4	GERP 2.6, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 1,226 bp · p 0.00025 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PI4KB
Protein: p.Met754Arg
Coding: c.2261T>G
MANE Select: NM_001369623
dbSNP: rs2528612732
Type: single nucleotide variant
Location: chr1:151294026 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.97 · 20 PDB
Residue 754: the pi3k/pi4k catalytic domain; a UniProt-annotated variant site (in dfna87; uncertain significance; unable to rescue defective inner ear phenotype and sound stimuli response in zebrafish morphants); an α-helix

Full PI4KB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hearing loss, autosomal dominant 87 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PI4KB p.Tyr175Cys Uncertain significance ★★ ⚠ same condition
PI4KB p.Gln121Arg Pathogenic ⚠ same condition
PI4KB p.Glu682Lys Pathogenic ⚠ same condition
PI4KB p.Val449Gly Pathogenic same condition
PI4KB p.Ile312Val Uncertain significance ★★ ⚠ same type
PI4KB c.-17G>A Uncertain significance ★ same type
PI4KB c.-6G>T Uncertain significance ★ same type
PI4KB p.Ala106Val 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/pi4kb-p-met754arg (accessed [today's date]).

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