Is KAT6B p.Leu577Phe (c.1731A>T) pathogenic?

KAT6B p.Leu577Phe (c.1731A>T) is classified Uncertain significance in KAT6B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.0508); Very rare (popmax 0.005%, amr); Associated with genitopatellar syndrome.

What condition is associated with KAT6B p.Leu577Phe (c.1731A>T)?

KAT6B p.Leu577Phe (c.1731A>T) is associated with genitopatellar syndrome (ClinVar).

How common is KAT6B p.Leu577Phe (c.1731A>T) in the general population?

KAT6B p.Leu577Phe (c.1731A>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about KAT6B p.Leu577Phe (c.1731A>T)?

AlphaMissense predicts likely benign (score 0.0508) — an in-silico prediction, not a clinical call.

KAT6B p.Leu577Phe

c.1731A>T · VCV4812117

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0508 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

genitopatellar syndrome

Computational evidence

Protein change
AlphaMissense	0.0508	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -6.74	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 -1.3	GERP -3.8
Regional constraint	o/e 0.82	unconstrained · MANE · 9,183 bp · p 4.6e-05 · regional, not allelic
Overall
CADD	6.424	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 0.005% Admixed American · 3/60,026 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000248% 4/1,614,202 alleles · very rare exomes 3/1,461,886 · genomes 1/152,316 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,009
African / African-American	0.00133%	75,040

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: KAT6B
Protein: p.Leu577Phe
Coding: c.1731A>T
MANE Select: NM_012330
Type: single nucleotide variant
Location: chr10:74976068 (GRCh38)
Gene constraint: LOEUF 0.098 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.67 · 3 PDB
Residue 577: the 'disordered' region; the 'negatively regulates hat activity' region

Full KAT6B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

genitopatellar syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KAT6B c.3664+1G>A Pathogenic ★★ same condition
KAT6B p.Arg1058Ter Pathogenic ★★ same condition
KAT6B p.Arg1797Ter Pathogenic ★★ same condition
KAT6B p.Gln1752Ter Pathogenic ★★ same condition
KAT6B c.2373+6C>A Uncertain significance ★★ same condition
KAT6B c.2374-3T>C Uncertain significance ★★ same condition
KAT6B p.Ala1317Thr Uncertain significance ★★ ⚠ same condition
KAT6B p.Ala1498Ser 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/kat6b-p-leu577phe (accessed [today's date]).

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