FBXO38

Chr 5AD

F-box protein 38

Also known as: Fbx38, HMN2D, HMND6, MOKA, SP329

NCBI Gene: 81545 ENSG00000145868 UniProt: Q6PIJ6 OMIM: 608533

This gene encodes a substrate recognition component of an E3 ubiquitin ligase complex that mediates proteasomal degradation of target proteins and acts as a transcriptional co-activator of KLF7, a regulator of neuronal differentiation. Heterozygous mutations cause autosomal dominant distal hereditary motor neuronopathy type IID, which affects peripheral motor neurons. The gene is highly constrained against loss-of-function variants (pLI=1.0, LOEUF=0.27), indicating that biallelic loss-of-function mutations are likely incompatible with life.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a large protein that contains an F-box domain and may participate in protein ubiquitination. The encoded protein is a transcriptional co-activator of Krueppel-like factor 7 (Klf7). A heterozygous mutation in this gene was found in individuals with autosomal dominant distal hereditary motor neuronopathy type IID. There is a pseudogene for this gene on chromosome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neuronopathy, distal hereditary motor, autosomal dominant 6MIM #615575

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · distal hereditary motor neuropathy · AD · ClinGen 2026

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.27

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.27LOEUF

pLI 0.999

Z-score 6.05

OE 0.15 (0.09–0.27)

Highly constrained

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

Missense Constraint?

2.81Z-score

OE missense 0.68 (0.63–0.74)

425 obs / 622.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.15 (0.09–0.27)

0≤0.351.4

Missense OE?0.68 (0.63–0.74)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 9 / 59.2Missense obs/exp: 425 / 622.5Syn Z: 0.56

Background carrier burden — how many people carry a rare variant somewhere in FBXO38?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 52

1,161 rare PASS variants

Rare truncating (LoF)

1 in 3,700

97 rare PASS variants

Rare synonymous (reference)

1 in 210

492 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FBXO38. 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 58	1 in 4,200
South Asian	~43k	1 in 48	≈ 1 in 9,700
Remaining (unassigned)	~30k	1 in 52	≈ 1 in 30,000
European (Finnish)	~27k	1 in 220	1 in 4,400
Admixed American	~22k	1 in 49	1 in 2,100
African / African American	~21k	1 in 47	1 in 1,400
East Asian	~20k	1 in 70	1 in 2,100
Ashkenazi Jewish	~13k	1 in 180	none seen
Middle Eastern	~2,884	1 in 59	≈ 1 in 2,800

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): 18 of 21 coding exons well covered in gnomAD exomes; exons 8, 17, 20 marginal. Genomes: all 21.? see exons ↓