TTC5

Chr 14AR

tetratricopeptide repeat domain 5

Also known as: NEDCAFD, Strap

NCBI Gene: 91875 ENSG00000136319 UniProt: Q8N0Z6 OMIM: 619014

TTC5 encodes a cofactor protein that regulates multiple cellular processes including actin dynamics, autophagy, DNA damage response, and mitochondrial ATP production through interactions with various protein complexes. Mutations in TTC5 cause autosomal recessive intellectual disability with microcephaly, seizures, and spasticity, typically presenting in early childhood. The gene shows very low constraint against loss-of-function variants (pLI near 0), consistent with recessive inheritance where heterozygous carriers are unaffected.

OMIM ResearchSummary from RefSeq, UniProt

Enables ribosome binding activity. Involved in positive regulation of mRNA catabolic process. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphismMIM #619244

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.79

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.79LOEUF

pLI 0.000

Z-score 2.37

OE 0.50 (0.32–0.79)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.53Z-score

OE missense 0.90 (0.81–1.01)

216 obs / 239.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.32–0.79)

0≤0.351.4

Missense OE?0.90 (0.81–1.01)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 13 / 26.0Missense obs/exp: 216 / 239.1Syn Z: -0.06

Background carrier burden — how many people carry a rare variant somewhere in TTC5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

534 rare PASS variants

Rare truncating (LoF)

1 in 2,000

94 rare PASS variants

Rare synonymous (reference)

1 in 150

198 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TTC5. 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 130	1 in 1,900
South Asian	~43k	1 in 110	1 in 2,500
Remaining (unassigned)	~30k	1 in 120	1 in 780
European (Finnish)	~27k	1 in 210	1 in 3,800
Admixed American	~22k	1 in 170	≈ 1 in 5,100
African / African American	~21k	1 in 130	1 in 2,100
East Asian	~20k	1 in 110	1 in 750
Ashkenazi Jewish	~13k	1 in 310	none seen
Middle Eastern	~2,884	1 in 96	≈ 1 in 2,900

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): All 10 coding exons well covered in gnomAD exomes and genomes.? see exons ↓