Is KDM6B p.Arg135Pro (c.404G>C) pathogenic?

KDM6B p.Arg135Pro (c.404G>C) is classified Uncertain significance in KDM6B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.7796); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with KDM6B p.Arg135Pro (c.404G>C)?

KDM6B p.Arg135Pro (c.404G>C) is associated with Inborn genetic diseases (ClinVar).

How common is KDM6B p.Arg135Pro (c.404G>C) in the general population?

KDM6B p.Arg135Pro (c.404G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KDM6B p.Arg135Pro (c.404G>C)?

AlphaMissense predicts likely pathogenic (score 0.7796) — an in-silico prediction, not a clinical call.

KDM6B p.Arg135Pro

c.404G>C · VCV4091393

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7796 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7796	likely pathogenic
REVEL	0.25	benign-leaning
SaProt	LLR -15.07	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,302 bp · p 0.47 · regional, not allelic
Overall
CADD	25.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: KDM6B
Protein: p.Arg135Pro
Coding: c.404G>C
MANE Select: NM_001348716
Type: single nucleotide variant
Location: chr17:7846245 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.54 · 6 PDB
Residue 135: a UniProt-annotated variant site (in nedsst)

Full KDM6B 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

KDM6B p.Arg135Ter Pathogenic ★ same residue
KDM6B p.Ala1219Val Uncertain significance ★★ ⚠ same condition
KDM6B p.Ala808Ser Uncertain significance ★★ ⚠ same condition
KDM6B p.Ala884Gly Uncertain significance ★★ ⚠ same condition
KDM6B p.Arg1566His Uncertain significance ★★ ⚠ same condition
KDM6B p.Arg306Trp Uncertain significance ★★ ⚠ same condition
KDM6B p.Arg475Ser Uncertain significance ★★ ⚠ same condition
KDM6B p.Arg478Cys 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-arg135pro (accessed [today's date]).

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