Is KAT8 p.Pro309Leu (c.926C>T) pathogenic?

KAT8 p.Pro309Leu (c.926C>T) is classified Uncertain significance in KAT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-29). AlphaMissense: likely pathogenic (0.7721); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KAT8 p.Pro309Leu (c.926C>T)?

KAT8 p.Pro309Leu (c.926C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KAT8 p.Pro309Leu (c.926C>T) in the general population?

KAT8 p.Pro309Leu (c.926C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about KAT8 p.Pro309Leu (c.926C>T)?

AlphaMissense predicts likely pathogenic (score 0.7721) — an in-silico prediction, not a clinical call.

KAT8 p.Pro309Leu

c.926C>T · rs771121616 · VCV3112784

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7721 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7721	likely pathogenic
REVEL	0.17	moderately benign-leaning
SaProt	LLR -7.74	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 7.7	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	23.0	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 0.000169% European (non-Finnish) · 2/1,180,022 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,614,036 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,020
European (non-Finnish)grpmax	0.000169%	590,012

Finnish 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.Pro309Leu
Coding: c.926C>T
MANE Select: NM_032188
dbSNP: rs771121616
Type: single nucleotide variant
Location: chr16:31130280 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 44 PDB
Residue 309: 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.Pro309Ser Uncertain significance ★ ⚠ same residue
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

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-pro309leu (accessed [today's date]).

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