Is KDM6B p.Leu725Val (c.2173C>G) pathogenic?

KDM6B p.Leu725Val (c.2173C>G) is classified Uncertain significance in KDM6B (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-31). AlphaMissense: likely benign (0.0763); Ultra-rare (popmax 0.045%, sas); Associated with neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities.

How common is KDM6B p.Leu725Val (c.2173C>G) in the general population?

KDM6B p.Leu725Val (c.2173C>G) is ultra-rare (popmax 0.045%, sas) (gnomAD).

What do computational predictors say about KDM6B p.Leu725Val (c.2173C>G)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

KDM6B p.Leu725Val

Q: What condition is associated with KDM6B p.Leu725Val (c.2173C>G)?

KDM6B p.Leu725Val (c.2173C>G) is associated with neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities (ClinVar).

c.2173C>G · rs745461436 · VCV2433077

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -2.9, phastCons 0.94
Regional constraint	o/e 1.08	unconstrained · MANE · 3,043 bp · p 0.0038 · regional, not allelic
Overall
CADD	11.34	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.045% South Asian · 41/91,064 alleles

Filtering AF 0.0341% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.00267% 43/1,611,972 alleles · ultra-rare exomes 42/1,460,048 · genomes 1/151,924 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.045%	2,221
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)	8.48e-05%	1,179,930

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.Leu725Val
Coding: c.2173C>G
MANE Select: NM_001348716
dbSNP: rs745461436
Type: single nucleotide variant
Location: chr17:7848461 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.54 · 6 PDB
Residue 725: a UniProt-annotated variant site (in nedsst); the 'disordered' region

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

Disease context

neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KDM6B p.Leu725Pro Uncertain significance ★ ⚠ same residue
KDM6B p.Arg1499Ter Pathogenic/Likely pathogenic ★★ same condition
KDM6B p.Arg166Ter Pathogenic ★★ same condition
KDM6B p.Arg199Ter Pathogenic/Likely pathogenic ★★ same condition
KDM6B p.Arg229Ter Pathogenic/Likely pathogenic ★★ same condition
KDM6B p.Arg495Ter Pathogenic/Likely pathogenic ★★ same condition
KDM6B p.Ala750Thr Uncertain significance ★★ ⚠ same condition
KDM6B p.Ala808Ser 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-leu725val (accessed [today's date]).

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