Is KAT8 p.Ala47Glu (c.140C>A) pathogenic?

KAT8 p.Ala47Glu (c.140C>A) is classified Uncertain significance in KAT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). AlphaMissense: likely benign (0.1345); Ultra-rare (popmax 0.0207%, sas); Associated with Li-Ghorbani-Weisz-Hubshman syndrome.

What condition is associated with KAT8 p.Ala47Glu (c.140C>A)?

KAT8 p.Ala47Glu (c.140C>A) is associated with Li-Ghorbani-Weisz-Hubshman syndrome (ClinVar).

How common is KAT8 p.Ala47Glu (c.140C>A) in the general population?

KAT8 p.Ala47Glu (c.140C>A) is ultra-rare (popmax 0.0207%, sas) (gnomAD).

What do computational predictors say about KAT8 p.Ala47Glu (c.140C>A)?

AlphaMissense predicts likely benign (score 0.1345) — an in-silico prediction, not a clinical call.

KAT8 p.Ala47Glu

c.140C>A · VCV3603271

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1345 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0207%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Li-Ghorbani-Weisz-Hubshman syndrome

Computational evidence

Protein change
AlphaMissense	0.1345	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 139 bp · p 0.14 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0207% South Asian · 15/72,330 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0103%

Overall 0.00118% 17/1,435,378 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0207%	4,822
Remaining individualsnot grpmax-eligible	0.00368%	27,179

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.Ala47Glu
Coding: c.140C>A
MANE Select: NM_032188
Type: single nucleotide variant
Location: chr16:31117821 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 44 PDB
Residue 47: the 'disordered' 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.Arg224Cys Uncertain significance ★ ⚠ same condition
KAT8 p.Arg233Trp 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-ala47glu (accessed [today's date]).

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