Is KAT8 p.Arg99Gln (c.296G>A) pathogenic?

KAT8 p.Arg99Gln (c.296G>A) is classified Likely pathogenic in KAT8 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-01-31). AlphaMissense: likely pathogenic (0.9995); Very rare (popmax 8.48e-05%, nfe); Associated with KAT8-related disorder.

What condition is associated with KAT8 p.Arg99Gln (c.296G>A)?

KAT8 p.Arg99Gln (c.296G>A) is associated with KAT8-related disorder (ClinVar).

How common is KAT8 p.Arg99Gln (c.296G>A) in the general population?

KAT8 p.Arg99Gln (c.296G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about KAT8 p.Arg99Gln (c.296G>A)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

KAT8 p.Arg99Gln

c.296G>A · rs2143966454 · VCV1690352

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

KAT8-related disorder

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic ✓ concordant with ClinVar
REVEL	0.581	indeterminate
SaProt	LLR -15.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 2,641 bp · p 2.7e-07 · 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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,760 alleles

Overall 6.84e-05% 1/1,461,568 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: KAT8
Protein: p.Arg99Gln
Coding: c.296G>A
MANE Select: NM_032188
dbSNP: rs2143966454
Type: single nucleotide variant
Location: chr16:31120348 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 44 PDB
Residue 99: the tudor-knot domain; a UniProt-annotated variant site (in ligows; no effect on protein expression; no effect on msl complex assembly; decreased histone acetyltransferase activity)

Full KAT8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

KAT8-related disorder

Similar variants

KAT8 p.Arg99Trp Conflicting classifications of pathogenicity ★ same residue
KAT8 c.1006+5G>C Uncertain significance ★ same condition
KAT8 c.212-2A>G Uncertain significance ★ same condition
KAT8 p.Ile189Thr Uncertain significance ⚠ same condition
KAT8 p.Tyr212Ter Uncertain significance same condition
KAT8 c.1312+50A>G Benign same condition
KAT8 p.Gly311Leu Uncertain significance same condition
KAT8 p.Tyr90Cys Likely pathogenic ★★ 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/kat8-p-arg99gln (accessed [today's date]).

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