TTLL1

Chr 22

TTL family tubulin polyglutamylase complex subunit L1

Also known as: C22orf7, HS323M22B, TPGS3

NCBI Gene: 25809 ENSG00000100271 UniProt: O95922 OMIM: 608955

This gene encodes a catalytic subunit of a polyglutamylase complex that modifies tubulin by adding glutamate side chains, which is essential for cilia and flagella biogenesis and motility. Mutations cause autosomal recessive primary ciliary dyskinesia, a disorder affecting respiratory cilia function and sperm motility. The gene shows low constraint to loss-of-function variants (pLI near 0), consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, UniProt

Enables tubulin-glutamic acid ligase activity. Involved in microtubule cytoskeleton organization. Is active in microtubule. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.87

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.000

Z-score 2.03

OE 0.54 (0.34–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.46Z-score

OE missense 0.74 (0.66–0.84)

194 obs / 260.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.34–0.87)

0≤0.351.4

Missense OE?0.74 (0.66–0.84)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 12 / 22.3Missense obs/exp: 194 / 260.5Syn Z: -0.66

Background carrier burden — how many people carry a rare variant somewhere in TTLL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

521 rare PASS variants

Rare truncating (LoF)

1 in 2,200

77 rare PASS variants

Rare synonymous (reference)

1 in 140

246 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TTLL1. 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 200	1 in 2,400
South Asian	~43k	1 in 120	1 in 2,700
Remaining (unassigned)	~30k	1 in 160	1 in 2,100
European (Finnish)	~27k	1 in 990	1 in 4,400
Admixed American	~22k	1 in 110	1 in 3,200
African / African American	~21k	1 in 140	1 in 2,300
East Asian	~20k	1 in 110	1 in 1,000
Ashkenazi Jewish	~13k	1 in 370	none seen
Middle Eastern	~2,884	1 in 100	≈ 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): 8 of 9 coding exons well covered in gnomAD exomes; exon 5 marginal. Genomes: all 9.? see exons ↓