KLHL35

Chr 11

kelch like family member 35

NCBI Gene: 283212 ENSG00000149243 UniProt: Q6PF15

The protein functions as an adaptor in the Cul3-RING ubiquitin ligase complex, facilitating the targeting of specific proteins for degradation through the proteasome pathway. Mutations in this gene cause autosomal recessive intellectual disability with seizures and behavioral abnormalities. This gene is not highly constrained against loss-of-function mutations.

ResearchSummary from RefSeq

Predicted to enable ubiquitin-like ligase-substrate adaptor activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be part of Cul3-RING ubiquitin ligase complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.90

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.90LOEUF

pLI 0.000

Z-score -1.47

OE 1.44 (0.99–1.90)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.15Z-score

OE missense 1.03 (0.92–1.15)

226 obs / 219.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.44 (0.99–1.90)

0≤0.351.4

Missense OE?1.03 (0.92–1.15)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 19 / 13.2Missense obs/exp: 226 / 219.7Syn Z: 0.72

Background carrier burden — how many people carry a rare variant somewhere in KLHL35?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 48

1,123 rare PASS variants

Rare truncating (LoF)

1 in 470

190 rare PASS variants

Rare synonymous (reference)

1 in 100

499 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KLHL35. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 64	1 in 500
South Asian	~43k	1 in 38	1 in 310
Remaining (unassigned)	~30k	1 in 35	1 in 540
European (Finnish)	~27k	1 in 120	1 in 1,900
Admixed American	~22k	1 in 38	1 in 220
African / African American	~21k	1 in 44	1 in 200
East Asian	~20k	1 in 46	1 in 410
Ashkenazi Jewish	~13k	1 in 110	≈ 1 in 3,800
Middle Eastern	~2,884	1 in 56	≈ 1 in 630

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 5 of 6 coding exons well covered in gnomAD exomes; exon 2 marginal. Genomes: all 6.? see exons ↓