Is KAT6A p.Pro535Ser (c.1603C>T) pathogenic?

KAT6A p.Pro535Ser (c.1603C>T) is classified Conflicting classifications of pathogenicity in KAT6A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-25). AlphaMissense: likely pathogenic (0.8486); Very rare (popmax 0.00746%, nfe).

How common is KAT6A p.Pro535Ser (c.1603C>T) in the general population?

KAT6A p.Pro535Ser (c.1603C>T) is very rare (popmax 0.00746%, nfe) (gnomAD).

What do computational predictors say about KAT6A p.Pro535Ser (c.1603C>T)?

AlphaMissense predicts likely pathogenic (score 0.8486) — an in-silico prediction, not a clinical call.

KAT6A p.Pro535Ser

c.1603C>T · rs753999434 · VCV1696946

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8486 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00746%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8486	likely pathogenic
REVEL	0.416	indeterminate
SaProt	LLR -8.36	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 7,470 bp · p 7.1e-06 · regional, not allelic
Overall
CADD	24.2	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 0.00746% European (non-Finnish) · 85/1,139,986 alleles

Filtering AF 0.00617% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00568%

Overall 0.00624% 95/1,522,354 alleles · very rare exomes 89/1,370,378 · genomes 6/151,976 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0102%	9,760
European (non-Finnish)grpmax	0.00746%	13,412
African / African-American	0.00572%	17,497

Remaining individuals 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: KAT6A
Protein: p.Pro535Ser
Coding: c.1603C>T
MANE Select: NM_006766
dbSNP: rs753999434
Type: single nucleotide variant
Location: chr8:41949359 (GRCh38)
Gene constraint: LOEUF 0.083 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.12 · 21 PDB
Residue 535: the 'interaction with runx1-1' region; a β-strand; the 'catalytic' region; the 'mediates interaction with brpf1, required for histone h3 acetyltransferase activity' region; the myst-type hat domain; the 'interaction with pml' region

Full KAT6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KAT6A p.Pro535= Likely benign ★ same residue
KAT6A c.3353-1G>A Pathogenic/Likely pathogenic ★★ same type
KAT6A p.Arg1012Ter Pathogenic ★★ same type
KAT6A p.Arg1019Ter Pathogenic/Likely pathogenic ★★ same type
KAT6A p.Arg1024Ter Pathogenic ★★ same type
KAT6A p.Arg1129Ter Pathogenic ★★ same type
KAT6A p.Arg148Ter Pathogenic ★★ same type
KAT6A p.Arg220Ter Pathogenic/Likely 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/kat6a-p-pro535ser (accessed [today's date]).

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