Is KAT8 p.Phe331Leu (c.993C>G) pathogenic?

KAT8 p.Phe331Leu (c.993C>G) is classified Uncertain significance in KAT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-30). AlphaMissense: likely pathogenic (0.9549); Absent from gnomAD v4.1.

How common is KAT8 p.Phe331Leu (c.993C>G) in the general population?

KAT8 p.Phe331Leu (c.993C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KAT8 p.Phe331Leu (c.993C>G)?

AlphaMissense predicts likely pathogenic (score 0.9549) — an in-silico prediction, not a clinical call.

KAT8 p.Phe331Leu

c.993C>G · VCV3373262

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9549 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9549	likely pathogenic
REVEL	0.237	benign-leaning
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	GERP -5.2, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 3,292 bp · p 4.6e-08 · regional, not allelic
Overall
CADD	13.77	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

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.Phe331Leu
Coding: c.993C>G
MANE Select: NM_032188
Type: single nucleotide variant
Location: chr16:31130347 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 44 PDB
Residue 331: 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; an α-helix

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

Similar variants

KAT8 p.Tyr90Cys Likely pathogenic ★★ same type
KAT8 p.Arg144His Uncertain significance ★★ ⚠ same type
KAT8 p.Gly19Arg Uncertain significance ★★ ⚠ same type
KAT8 p.Ile57Val Uncertain significance ★★ ⚠ same type
KAT8 p.Lys203Ter Uncertain significance ★★ same type
KAT8 p.Leu370= Benign ★★ same type
KAT8 p.Pro352= Benign ★★ same type
KAT8 p.Arg108Trp Pathogenic ★ same type

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-phe331leu (accessed [today's date]).

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