Is KAT8 p.Pro235Arg (c.704C>G) pathogenic?

KAT8 p.Pro235Arg (c.704C>G) is classified Uncertain significance in KAT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1.

How common is KAT8 p.Pro235Arg (c.704C>G) in the general population?

KAT8 p.Pro235Arg (c.704C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KAT8 p.Pro235Arg (c.704C>G)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

KAT8 p.Pro235Arg

c.704C>G · VCV3368299

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic
REVEL	0.811	moderately pathogenic-leaning
SaProt	LLR -16.89	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	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	27.2	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.Pro235Arg
Coding: c.704C>G
MANE Select: NM_032188
Type: single nucleotide variant
Location: chr16:31128072 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 44 PDB
Residue 235: 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

Similar variants

KAT8 p.Pro235= Likely benign ★ same residue
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

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-pro235arg (accessed [today's date]).

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