TTC39A

Chr 1

tetratricopeptide repeat domain 39A

Also known as: C1orf34, DEME-6

NCBI Gene: 22996 ENSG00000085831 UniProt: Q5SRH9

TTC39A encodes a protein located in the centrosome, a cellular structure critical for cell division and cilia formation. Mutations in this gene cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, affecting the nervous system and brain development. The gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely pathogenic.

ResearchSummary from RefSeq

Located in centrosome. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.56

Clinical Summary— TTC39A

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.35) despite low pLI — interpret in context.

📋

ClinVar Variants

59 VUS of 82 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.56LOEUF

pLI 0.001

Z-score 3.58

OE 0.35 (0.22–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.28Z-score

OE missense 0.64 (0.57–0.72)

203 obs / 317.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.35 (0.22–0.56)

0≤0.351.4

Missense OE?0.64 (0.57–0.72)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 12 / 34.8Missense obs/exp: 203 / 317.3Syn Z: 0.95

This gene — mechanism propensity

0.6841th %ile

GOF

0.6638th %ile

LOF

0.3068th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

82 submitted variants in ClinVar

ClinVar

Classification Summary

VUS59

Likely Benign4

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	59	0	59
Likely Benign	2	2	4
Benign	0	0	0
Total	61	2	63

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap TTC39A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →