Is KDM6B p.Ala1237Val (c.3710C>T) pathogenic?

KDM6B p.Ala1237Val (c.3710C>T) is classified Uncertain significance in KDM6B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-09). AlphaMissense: likely pathogenic (0.7887); Very rare (popmax 0.00373%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KDM6B p.Ala1237Val (c.3710C>T)?

KDM6B p.Ala1237Val (c.3710C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KDM6B p.Ala1237Val (c.3710C>T) in the general population?

KDM6B p.Ala1237Val (c.3710C>T) is very rare (popmax 0.00373%, nfe) (gnomAD).

What do computational predictors say about KDM6B p.Ala1237Val (c.3710C>T)?

AlphaMissense predicts likely pathogenic (score 0.7887) — an in-silico prediction, not a clinical call.

KDM6B p.Ala1237Val

c.3710C>T · rs374474605 · VCV2400166

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7887	likely pathogenic
REVEL	0.362	indeterminate
SaProt	LLR -5.39	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 924 bp · p 0.058 · regional, not allelic
Overall
CADD	28.5	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 0.00373% European (non-Finnish) · 44/1,179,594 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00279% 45/1,612,444 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00373%	26,809
Remaining individualsnot grpmax-eligible	0.0016%	62,454

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.Ala1237Val
Coding: c.3710C>T
MANE Select: NM_001348716
dbSNP: rs374474605
Type: single nucleotide variant
Location: chr17:7851057 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.54 · 6 PDB
Residue 1237: a UniProt-annotated variant site (in nedsst); an α-helix

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.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
KDM6B p.Arg492Trp 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-ala1237val (accessed [today's date]).

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