Is KAT8 p.Ser428Arg (c.1284T>G) pathogenic?

KAT8 p.Ser428Arg (c.1284T>G) is classified Uncertain significance in KAT8 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9931); Absent from gnomAD v4.1; Associated with Li-Ghorbani-Weisz-Hubshman syndrome.

What condition is associated with KAT8 p.Ser428Arg (c.1284T>G)?

KAT8 p.Ser428Arg (c.1284T>G) is associated with Li-Ghorbani-Weisz-Hubshman syndrome (ClinVar).

How common is KAT8 p.Ser428Arg (c.1284T>G) in the general population?

KAT8 p.Ser428Arg (c.1284T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KAT8 p.Ser428Arg (c.1284T>G)?

AlphaMissense predicts likely pathogenic (score 0.9931) — an in-silico prediction, not a clinical call.

KAT8 p.Ser428Arg

c.1284T>G · rs2544179460 · VCV3236405

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9931 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Li-Ghorbani-Weisz-Hubshman syndrome

Computational evidence

Protein change
AlphaMissense	0.9931	likely pathogenic
REVEL	0.31	indeterminate
SaProt	LLR -11.59	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 -0.19	GERP -4.4, phastCons 0.64
Regional constraint	o/e 0.71	unconstrained · MANE · 688 bp · p 0.0028 · regional, not allelic
Overall
CADD	19.02	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

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.Ser428Arg
Coding: c.1284T>G
MANE Select: NM_032188
dbSNP: rs2544179460
Type: single nucleotide variant
Location: chr16:31130872 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 44 PDB
Residue 428: 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

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-ser428arg (accessed [today's date]).

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