Is KAT8 p.Val299Phe (c.895G>T) pathogenic?

KAT8 p.Val299Phe (c.895G>T) is classified Uncertain significance in KAT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-20). AlphaMissense: likely pathogenic (0.997); Very rare (popmax 0.0071%, afr); Associated with Li-Ghorbani-Weisz-Hubshman syndrome.

What condition is associated with KAT8 p.Val299Phe (c.895G>T)?

KAT8 p.Val299Phe (c.895G>T) is associated with Li-Ghorbani-Weisz-Hubshman syndrome (ClinVar).

How common is KAT8 p.Val299Phe (c.895G>T) in the general population?

KAT8 p.Val299Phe (c.895G>T) is very rare (popmax 0.0071%, afr) (gnomAD).

What do computational predictors say about KAT8 p.Val299Phe (c.895G>T)?

AlphaMissense predicts likely pathogenic (score 0.997) — an in-silico prediction, not a clinical call.

KAT8 p.Val299Phe

c.895G>T · VCV3341460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.997 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0071%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Li-Ghorbani-Weisz-Hubshman syndrome

Computational evidence

Protein change
AlphaMissense	0.997	likely pathogenic
REVEL	0.9	moderately pathogenic-leaning
SaProt	LLR -14.78	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 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 3,292 bp · p 4.6e-08 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0071% African / African-American · 5/70,424 alleles

Filtering AF 0.00277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00181%

Overall 0.000319% 5/1,567,454 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.Val299Phe
Coding: c.895G>T
MANE Select: NM_032188
Type: single nucleotide variant
Location: chr16:31130140 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 44 PDB
Residue 299: the myst-type hat domain; a UniProt-annotated variant site (found in a severe neurodevelopmental disorder similar to li-ghorbani-weisz-hubshman syndrome with apparently autosomal recessive inheritance; uncertain significance; loss of protein expression); the 'sufficient for interaction with kansl1' region; a β-strand

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

Disease context

Li-Ghorbani-Weisz-Hubshman syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KAT8 p.Tyr90Cys Likely pathogenic ★★ same condition
KAT8 p.Gly19Arg Uncertain significance ★★ ⚠ same condition
KAT8 p.Ile57Val Uncertain significance ★★ ⚠ same condition
KAT8 p.His92Arg Pathogenic ★ same condition
KAT8 p.Lys175Thr Likely pathogenic ★ same condition
KAT8 c.1312+24C>G Conflicting classifications of pathogenicity ★ same condition
KAT8 p.Ala47Glu Uncertain significance ★ ⚠ same condition
KAT8 p.Arg224Cys Uncertain significance ★ ⚠ same condition

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-val299phe (accessed [today's date]).

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