Is KAT8 p.Arg99Trp (c.295C>T) pathogenic?

KAT8 p.Arg99Trp (c.295C>T) is classified Conflicting classifications of pathogenicity in KAT8 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-22). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1.

How common is KAT8 p.Arg99Trp (c.295C>T) in the general population?

KAT8 p.Arg99Trp (c.295C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KAT8 p.Arg99Trp (c.295C>T)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

KAT8 p.Arg99Trp

c.295C>T · rs2544163458 · VCV3253327

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic
REVEL	0.654	pathogenic-leaning
SaProt	LLR -16.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	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	29.1	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: KAT8
Protein: p.Arg99Trp
Coding: c.295C>T
MANE Select: NM_032188
dbSNP: rs2544163458
Type: single nucleotide variant
Location: chr16:31120347 (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

Similar variants

KAT8 p.Arg99Gln Likely pathogenic ★ same residue
KAT8 p.Tyr90Cys Likely pathogenic ★★ same type
KAT8 p.Arg144His Uncertain significance ★★ ⚠ same type
KAT8 p.Gly19Arg Uncertain significance ★★ ⚠ same type
KAT8 p.Ile57Val Uncertain significance ★★ ⚠ same type
KAT8 p.Lys203Ter Uncertain significance ★★ same type
KAT8 p.Leu370= Benign ★★ same type
KAT8 p.Pro352= 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/kat8-p-arg99trp (accessed [today's date]).

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