TTLL2

Chr 6

tubulin tyrosine ligase like 2

Also known as: C6orf104, NYD-TSPG, dJ366N23.3

NCBI Gene: 83887 ENSG00000120440 UniProt: Q9BWV7 OMIM: 619410

The protein is a tubulin polyglutamylase that modifies tubulin by adding glutamate side chains to microtubules, which is important for microtubule function and ciliary structure. Mutations cause autosomal recessive retinal dystrophy and cone-rod dystrophy, affecting vision through photoreceptor degeneration. The gene shows tolerance to loss-of-function variants, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable tubulin binding activity and tubulin-glutamic acid ligase activity. Predicted to be involved in microtubule cytoskeleton organization. Predicted to be active in ciliary basal body. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Active trials

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Pubs (1 yr)

—

P/LP submissions

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P/LP missense

1.87

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.87LOEUF

pLI 0.006

Z-score -0.08

OE 1.05 (0.45–1.87)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.19Z-score

OE missense 0.97 (0.89–1.06)

320 obs / 329.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.05 (0.45–1.87)

0≤0.351.4

Missense OE?0.97 (0.89–1.06)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 3 / 2.8Missense obs/exp: 320 / 329.7Syn Z: -0.33

Background carrier burden — how many people carry a rare variant somewhere in TTLL2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 44

784 rare PASS variants

Rare truncating (LoF)

1 in 330

102 rare PASS variants

Rare synonymous (reference)

1 in 100

303 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TTLL2. 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 60	1 in 760
South Asian	~43k	1 in 49	1 in 410
Remaining (unassigned)	~30k	1 in 37	1 in 340
European (Finnish)	~27k	1 in 150	1 in 4,400
Admixed American	~22k	1 in 55	1 in 430
African / African American	~21k	1 in 46	1 in 440
East Asian	~20k	1 in 73	1 in 1,200
Ashkenazi Jewish	~13k	1 in 440	1 in 1,200
Middle Eastern	~2,884	1 in 56	1 in 180

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.