Is KAT8 p.Val251Ile (c.751G>A) pathogenic?

KAT8 p.Val251Ile (c.751G>A) is classified Uncertain significance in KAT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-03). AlphaMissense: likely benign (0.2631); Very rare (popmax 8.47e-05%, nfe); Associated with Li-Ghorbani-Weisz-Hubshman syndrome.

What condition is associated with KAT8 p.Val251Ile (c.751G>A)?

KAT8 p.Val251Ile (c.751G>A) is associated with Li-Ghorbani-Weisz-Hubshman syndrome (ClinVar).

How common is KAT8 p.Val251Ile (c.751G>A) in the general population?

KAT8 p.Val251Ile (c.751G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about KAT8 p.Val251Ile (c.751G>A)?

AlphaMissense predicts likely benign (score 0.2631) — an in-silico prediction, not a clinical call.

KAT8 p.Val251Ile

c.751G>A · VCV3891439

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2631 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Li-Ghorbani-Weisz-Hubshman syndrome

Computational evidence

Protein change
AlphaMissense	0.2631	likely benign
REVEL	0.214	benign-leaning
SaProt	LLR -6.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 3,292 bp · p 4.6e-08 · regional, not allelic
Overall
CADD	21.8	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 8.47e-05% European (non-Finnish) · 1/1,179,966 alleles

Overall 0.000137% 2/1,461,704 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	8.47e-05%	1,179,966

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val251Ile
Coding: c.751G>A
MANE Select: NM_032188
Type: single nucleotide variant
Location: chr16:31128119 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 44 PDB
Residue 251: 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.Val251Leu Uncertain significance ★ ⚠ same residue
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

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-val251ile (accessed [today's date]).

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