TTC39B

Chr 9

tetratricopeptide repeat domain 39B

Also known as: C9orf52

NCBI Gene: 158219 ENSG00000155158 UniProt: Q5VTQ0 OMIM: 613574

The protein regulates high density lipoprotein (HDL) cholesterol metabolism by promoting ubiquitination and degradation of oxysterol receptors. Mutations cause autosomal recessive intellectual disability with neurodegeneration and spasticity, typically presenting in early childhood with progressive motor and cognitive decline. This gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to be involved in several processes, including cholesterol homeostasis; negative regulation of cholesterol storage; and regulation of cholesterol efflux. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.97

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.97LOEUF

pLI 0.000

Z-score 1.69

OE 0.71 (0.53–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-1.30Z-score

OE missense 1.20 (1.10–1.30)

417 obs / 348.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.71 (0.53–0.97)

0≤0.351.4

Missense OE?1.20 (1.10–1.30)

0≤0.61.4

Synonymous OE?1.32

0≤1.21.6

LoF obs/exp: 29 / 40.6Missense obs/exp: 417 / 348.8Syn Z: -2.91

Background carrier burden — how many people carry a rare variant somewhere in TTC39B?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 53

1,046 rare PASS variants

Rare truncating (LoF)

1 in 410

193 rare PASS variants

Rare synonymous (reference)

1 in 94

402 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TTC39B. 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 74	1 in 430
South Asian	~43k	1 in 40	1 in 260
Remaining (unassigned)	~30k	1 in 39	1 in 490
European (Finnish)	~27k	1 in 190	1 in 580
Admixed American	~22k	1 in 49	1 in 340
African / African American	~21k	1 in 52	1 in 400
East Asian	~20k	1 in 110	1 in 280
Ashkenazi Jewish	~13k	1 in 330	1 in 830
Middle Eastern	~2,884	1 in 45	≈ 1 in 1,200

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): 17 of 20 coding exons well covered in gnomAD exomes; exons 5, 6, 8 marginal. Genomes: all 20.? see exons ↓