KLHL10

Chr 17AD

kelch like family member 10

Also known as: SPGF11

NCBI Gene: 317719 ENSG00000161594 UniProt: Q6JEL2

The protein encoded by this gene belongs to the kelch repeat-containing family, and contains an N-terminal BTB/POZ domain a BACK domain and six C-terminal kelch repeats. Kelch domains are thought to form a four stranded beta-sheet blade structure that can fold into a beta-propeller domain when multiple kelch repeats are found together. Mutations in this gene have been associated with oligozoospermia in some infertile males. [provided by RefSeq, Jul 2016]

Primary Disease Associations & Inheritance

Spermatogenic failure 11MIM #615081

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

2.7

Missense Z

0.31

LOEUF· LoF intolerant

Clinical Summary— KLHL10

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

7 Pathogenic / Likely Pathogenic· 54 VUS of 84 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.31LOEUF

pLI 0.979

Z-score 3.80

OE 0.10 (0.04–0.31)

Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

2.72Z-score

OE missense 0.59 (0.53–0.67)

213 obs / 358.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.10 (0.04–0.31)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.59 (0.53–0.67)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.09

0≤1.21.6

LoF obs/exp: 2 / 20.6Missense obs/exp: 213 / 358.0Syn Z: -0.79

0.5180th %ile

GOF

0.5562th %ile

LOF

0.58top 25%

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

LOF1 literature citation · LOEUF 0.31

Literature Evidence

LOFThe data demonstrated that, like protamine-1 (PRM1; 182880) and protamine-2 (PRM2; 182890), both alleles of Klhl10 are required for male fertility and that haploinsufficiency caused by a mutation in 1 allele of Klhl10 prevents genetic transmission of both mutant and wildtype alleles.PMID:15136734

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