Is PIP4K2A p.Lys89Arg (c.266A>G) pathogenic?

PIP4K2A p.Lys89Arg (c.266A>G) is classified Uncertain significance in PIP4K2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: likely benign (0.2704); Very rare (popmax 0.00167%, amr).

How common is PIP4K2A p.Lys89Arg (c.266A>G) in the general population?

PIP4K2A p.Lys89Arg (c.266A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PIP4K2A p.Lys89Arg (c.266A>G)?

AlphaMissense predicts likely benign (score 0.2704) — an in-silico prediction, not a clinical call.

PIP4K2A p.Lys89Arg

c.266A>G · VCV3932572

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2704 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2704	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -11.17	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 174 kb · p 0.019 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.00167% Admixed American · 1/59,944 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,611,688 alleles · very rare exomes 7/1,459,374 · genomes 0/152,314 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,944
European (non-Finnish)	0.000509%	196,343

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: PIP4K2A
Protein: p.Lys89Arg
Coding: c.266A>G
MANE Select: NM_005028
Type: single nucleotide variant
Location: chr10:22608000 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI 0.74 (gnomAD)
Structure: AlphaFold pLDDT 86.87 · 18 PDB
Residue 89: the pipk domain; a β-strand; a modified residue (n6-acetyllysine)

Full PIP4K2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PIP4K2A c.339+10G>A Benign ★★ same type
PIP4K2A p.Glu391= Benign ★★ same type
PIP4K2A p.Leu327Met Benign ★★ same type
PIP4K2A p.Ser304= Benign ★★ same type
PIP4K2A p.Ala383Thr Uncertain significance ★ ⚠ same type
PIP4K2A p.Arg133His Uncertain significance ★ ⚠ same type
PIP4K2A p.Arg203Cys Uncertain significance ★ same type
PIP4K2A p.Arg396His 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/pip4k2a-p-lys89arg (accessed [today's date]).

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