Is KAT8 p.His256Arg (c.767A>G) pathogenic?

KAT8 p.His256Arg (c.767A>G) is classified Uncertain significance in KAT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). AlphaMissense: likely pathogenic (0.7443); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KAT8 p.His256Arg (c.767A>G)?

KAT8 p.His256Arg (c.767A>G) is associated with Inborn genetic diseases (ClinVar).

How common is KAT8 p.His256Arg (c.767A>G) in the general population?

KAT8 p.His256Arg (c.767A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about KAT8 p.His256Arg (c.767A>G)?

AlphaMissense predicts likely pathogenic (score 0.7443) — an in-silico prediction, not a clinical call.

KAT8 p.His256Arg

c.767A>G · VCV4041169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7443 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7443	likely pathogenic
REVEL	0.394	indeterminate
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 3,292 bp · p 4.6e-08 · regional, not allelic
Overall
CADD	24.1	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

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,642 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,286 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.His256Arg
Coding: c.767A>G
MANE Select: NM_032188
Type: single nucleotide variant
Location: chr16:31128135 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 44 PDB
Residue 256: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KAT8 p.Tyr90Cys Likely pathogenic ★★ same condition
KAT8 p.Arg144His Uncertain significance ★★ ⚠ same condition
KAT8 p.Arg140Cys Pathogenic ★ same condition
KAT8 c.1312+12G>A Uncertain significance ★ same condition
KAT8 c.1312+16C>G Uncertain significance ★ same condition
KAT8 c.1312+25G>C Uncertain significance ★ same condition
KAT8 c.1312+31G>A Uncertain significance ★ same condition
KAT8 c.1312+58G>A 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-his256arg (accessed [today's date]).

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