KLHL15

Chr XXLR

kelch like family member 15

Also known as: HEL-S-305, XLID103

NCBI Gene: 80311 ENSG00000174010 UniProt: Q96M94 OMIM: 300980

The protein functions as a substrate-specific adapter for the CUL3 E3 ubiquitin-protein ligase complex, targeting specific proteins for degradation and playing a key role in DNA damage response by regulating DNA double-strand break repair pathways. Mutations cause X-linked intellectual developmental disorder with X-linked recessive inheritance. The gene is highly constrained against loss-of-function variants (pLI = 0.99, LOEUF = 0.20), indicating that functional variants are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the kelch-like family of proteins that share a common domain structure consisting of an N-terminal broad-complex, tramtrack, bric-a-brac/poxvirus and zinc finger domain and C-terminal kelch repeat motifs. The encoded protein may be involved in protein ubiquitination and cytoskeletal organization. [provided by RefSeq, Apr 2009]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLRLOEUF 0.201 OMIM phenotype

Clinical Summary— KLHL15

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 71 VUS of 143 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.20LOEUF

pLI 0.994

Z-score 3.63

OE 0.00 (0.00–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.69Z-score

OE missense 0.34 (0.28–0.41)

84 obs / 247.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.20)

0≤0.351.4

Missense OE?0.34 (0.28–0.41)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 0 / 15.3Missense obs/exp: 84 / 247.0Syn Z: -0.10

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedKLHL15-related intellectual disabilityLOFXLR

This gene — mechanism propensity

0.3196th %ile

GOF

0.4974th %ile

LOF

0.65top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.20

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

143 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS71

Likely Benign24

Benign4

Conflicting1

Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	0	0	0	0
VUS	3	67	0	1	71
Likely Benign	0	2	3	19	24
Benign	0	0	1	3	4
Conflicting	—				1
Total	3	70	4	23	101

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

60 pathogenic / likely-pathogenic (of 69) ClinVar copy-number / structural variants overlap KLHL15 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →