Is KDM6B p.Pro331= (c.993G>A) pathogenic?

KDM6B p.Pro331= (c.993G>A) is classified Likely benign in KDM6B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-25). Ultra-rare (popmax 0.0381%, afr); Associated with KDM6B-related disorder.

What condition is associated with KDM6B p.Pro331= (c.993G>A)?

KDM6B p.Pro331= (c.993G>A) is associated with KDM6B-related disorder (ClinVar).

How common is KDM6B p.Pro331= (c.993G>A) in the general population?

KDM6B p.Pro331= (c.993G>A) is ultra-rare (popmax 0.0381%, afr) (gnomAD).

KDM6B p.Pro331=

c.993G>A · rs375568952 · VCV3046417

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0381%, afr)

Conditions

KDM6B-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.56	GERP -0.7, phastCons 0.001
Overall
CADD	7.52	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0381% African / African-American · 28/73,440 alleles

Filtering AF 0.0271% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00369% 59/1,599,194 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0381%	2,623
East Asian	0.00895%	11,177
Admixed American	0.00837%	11,940
Remaining individualsnot grpmax-eligible	0.00642%	15,580
South Asian	0.0033%	30,279
Finnishnot grpmax-eligible	0.00184%	54,366
European (non-Finnish)	0.00119%	84,097

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: KDM6B
Protein: p.Pro331=
Coding: c.993G>A
MANE Select: NM_001348716
dbSNP: rs375568952
Type: single nucleotide variant
Location: chr17:7847188 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.54 · 6 PDB
Residue 331: the 'disordered' region; a UniProt-annotated variant site (in nedsst)

Full KDM6B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

KDM6B-related disorder

Similar variants

KDM6B p.Pro331Leu Uncertain significance ★ ⚠ same residue
KDM6B p.Arg951Ter Pathogenic ★★ same condition
KDM6B p.Pro37Leu Uncertain significance ★★ ⚠ same condition
KDM6B p.Cys1397Tyr Likely pathogenic ★ same condition
KDM6B p.Gln858Ter Likely pathogenic ★ same condition
KDM6B p.Trp41Ter Likely pathogenic ★ same condition
KDM6B p.Ala989Val Uncertain significance ★ ⚠ same condition
KDM6B p.Arg1551Pro 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/kdm6b-p-pro331 (accessed [today's date]).

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