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…

MultiplemechanismLOEUF 1.87

Clinical Summary— TTLL2

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

94 VUS of 109 total submissions

Explore recent and relevant literature in Research Assistant →

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

This gene — mechanism propensity

0.6550th %ile

GOF

0.6542th %ile

LOF

0.3259th %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

109 submitted variants in ClinVar

ClinVar

Classification Summary

VUS94

Likely Benign10

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	94	94
Likely Benign	10	10
Benign	2	2
Total	106	106

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

View in ClinVar →

59 pathogenic / likely-pathogenic (of 63) ClinVar copy-number / structural variants overlap TTLL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →