Is KAT6B p.Ser397Arg (c.1189A>C) pathogenic?

KAT6B p.Ser397Arg (c.1189A>C) is classified Uncertain significance in KAT6B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-24). AlphaMissense: likely pathogenic (0.9738); Very rare (popmax 0.00267%, afr); Associated with genitopatellar syndrome.

What condition is associated with KAT6B p.Ser397Arg (c.1189A>C)?

KAT6B p.Ser397Arg (c.1189A>C) is associated with genitopatellar syndrome, blepharophimosis - intellectual disability syndrome, SBBYS type (ClinVar).

How common is KAT6B p.Ser397Arg (c.1189A>C) in the general population?

KAT6B p.Ser397Arg (c.1189A>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about KAT6B p.Ser397Arg (c.1189A>C)?

AlphaMissense predicts likely pathogenic (score 0.9738) — an in-silico prediction, not a clinical call.

KAT6B p.Ser397Arg

c.1189A>C · rs1842093971 · VCV1499819

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

genitopatellar syndrome

Computational evidence

Protein change
AlphaMissense	0.9738	likely pathogenic · top 10% in KAT6B
REVEL	0.383	indeterminate
SaProt	LLR -7.26	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 9,183 bp · p 4.6e-05 · regional, not allelic
Overall
CADD	24.8	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 0.00267% African / African-American · 2/74,902 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,614,018 alleles · very rare

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.Ser397Arg
Coding: c.1189A>C
MANE Select: NM_012330
dbSNP: rs1842093971
Type: single nucleotide variant
Location: chr10:74975526 (GRCh38)
Gene constraint: LOEUF 0.098 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.67 · 3 PDB
Residue 397: 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

Also linked: blepharophimosis - intellectual disability syndrome, SBBYS type

Similar variants

KAT6B p.Ser397= Likely benign ★ same residue
KAT6B c.3664+1G>A Pathogenic ★★ same condition
KAT6B p.Arg1058Ter Pathogenic ★★ same condition
KAT6B p.Arg1797Ter Pathogenic ★★ same condition
KAT6B p.Arg783Ter Pathogenic/Likely pathogenic ★★ same condition
KAT6B p.Gln1014Ter Pathogenic ★★ same condition
KAT6B p.Gln1752Ter Pathogenic ★★ same condition
KAT6B p.Gln1768Ter Pathogenic ★★ 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-ser397arg (accessed [today's date]).

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