Is KDM6A p.Pro428= (c.1284C>T) pathogenic?

KDM6A p.Pro428= (c.1284C>T) is classified Benign/Likely benign in KDM6A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.0734%, afr); Associated with Kabuki syndrome 2.

What condition is associated with KDM6A p.Pro428= (c.1284C>T)?

KDM6A p.Pro428= (c.1284C>T) is associated with Kabuki syndrome 2 (ClinVar).

How common is KDM6A p.Pro428= (c.1284C>T) in the general population?

KDM6A p.Pro428= (c.1284C>T) is ultra-rare (popmax 0.0734%, afr) (gnomAD).

KDM6A p.Pro428=

c.1284C>T · rs147633358 · VCV712879

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0734%, afr)

Conditions

Kabuki syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.261	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.6, phastCons 1
Overall
CADD	14.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0734% African / African-American · 42/57,221 alleles

Filtering AF 0.0557% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0496%

Overall 0.00463% 56/1,209,649 alleles · ultra-rare exomes 36/1,097,704 · genomes 20/111,945 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0734%	1,362
Admixed American	0.00438%	22,857
Remaining individualsnot grpmax-eligible	0.0021%	47,594
European (non-Finnish)	0.00123%	81,372

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: KDM6A
Protein: p.Pro428=
Coding: c.1284C>T
MANE Select: NM_001291415
dbSNP: rs147633358
Type: single nucleotide variant
Location: chrX:45060111 (GRCh38)
Structure: AlphaFold pLDDT 71.55 · 5 PDB
Residue 428: the 'interaction with supt6h' region

Full KDM6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Kabuki syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KDM6A c.1581+1G>T Likely pathogenic ★★ same condition
KDM6A c.2988+1G>A Pathogenic ★★ same condition
KDM6A p.Arg1265Ter Pathogenic/Likely pathogenic ★★ same condition
KDM6A p.Arg1331Ter Pathogenic/Likely pathogenic ★★ same condition
KDM6A p.Arg1403Ter Pathogenic/Likely pathogenic ★★ same condition
KDM6A p.Arg1415Ter Pathogenic/Likely pathogenic ★★ same condition
KDM6A p.Arg165Ter Pathogenic ★★ same condition
KDM6A p.Arg172Ter 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/kdm6a-p-pro428 (accessed [today's date]).

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