Is KAT6A p.Pro1663Leu (c.4988C>T) pathogenic?

KAT6A p.Pro1663Leu (c.4988C>T) is classified Conflicting classifications of pathogenicity in KAT6A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.1343); Ultra-rare (popmax 0.014%, sas); Associated with Inborn genetic diseases.

What condition is associated with KAT6A p.Pro1663Leu (c.4988C>T)?

KAT6A p.Pro1663Leu (c.4988C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KAT6A p.Pro1663Leu (c.4988C>T) in the general population?

KAT6A p.Pro1663Leu (c.4988C>T) is ultra-rare (popmax 0.014%, sas) (gnomAD).

What do computational predictors say about KAT6A p.Pro1663Leu (c.4988C>T)?

AlphaMissense predicts likely benign (score 0.1343) — an in-silico prediction, not a clinical call.

KAT6A p.Pro1663Leu

c.4988C>T · rs755968563 · VCV589048

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1343 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.014%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1343	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -10.16	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP -2.1, phastCons 0.97
Regional constraint	o/e 0.87	unconstrained · MANE · 1,300 bp · p 0.0013 · regional, not allelic
Overall
CADD	8.173	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 0.014% South Asian · 12/85,600 alleles

Filtering AF 0.00805% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00628%

Overall 0.00348% 54/1,550,318 alleles · ultra-rare exomes 49/1,398,544 · genomes 5/151,774 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0319%	3,138
South Asiangrpmax	0.014%	7,133
Finnishnot grpmax-eligible	0.0118%	8,494
East Asian	0.00716%	13,968
Admixed American	0.00383%	26,095
Remaining individualsnot grpmax-eligible	0.00331%	30,175
African / African-American	0.00272%	36,799
European (non-Finnish)	0.00156%	63,973

Ashkenazi Jewish 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.Pro1663Leu
Coding: c.4988C>T
MANE Select: NM_006766
dbSNP: rs755968563
Type: single nucleotide variant
Location: chr8:41933232 (GRCh38)
Gene constraint: LOEUF 0.083 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.12 · 21 PDB
Residue 1663: the 'interaction with pml' region; the 'disordered' region

Full KAT6A 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

KAT6A p.Pro1663= Benign ★ same residue
KAT6A p.Arg1129Ter Pathogenic ★★ same condition
KAT6A p.Arg148Ter Pathogenic ★★ same condition
KAT6A p.Arg286Ter Pathogenic ★★ same condition
KAT6A p.Arg735Ter Pathogenic ★★ same condition
KAT6A p.Ala1451Gly Uncertain significance ★★ ⚠ same condition
KAT6A p.Ala492Val Uncertain significance ★★ ⚠ same condition
KAT6A p.Arg1086Ser 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/kat6a-p-pro1663leu (accessed [today's date]).

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