TMTC1

Chr 12

transmembrane O-mannosyltransferase targeting cadherins 1

Also known as: ARG99, OLF, TMTC1A

NCBI Gene: 83857ENSG00000133687UniProt: Q8IUR5

The TMTC1 protein transfers mannose residues to serine and threonine residues on cadherins and other proteins in the endoplasmic reticulum, playing a critical role in O-linked mannosylation. Mutations cause cobblestone lissencephaly-4 with microcephaly and profound intellectual disability, following an autosomal recessive inheritance pattern. This gene shows moderate constraint against loss-of-function variants, with the associated phenotype typically presenting in the neonatal period with severe brain malformations.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
7
Pubs (1 yr)
32
P/LP submissions
0%
P/LP missense
0.71
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— TMTC1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
32 unique Pathogenic / Likely Pathogenic· 132 VUS of 200 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
0.71LOEUF
pLI 0.000
Z-score 3.06
OE 0.50 (0.36–0.71)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.71Z-score
OE missense 0.91 (0.83–0.98)
409 obs / 451.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.50 (0.36–0.71)
0≤0.351.4
Missense OE0.91 (0.83–0.98)
0≤0.61.4
Synonymous OE1.06
0≤1.21.6
LoF obs/exp: 22 / 43.9Missense obs/exp: 409 / 451.5Syn Z: -0.67
DN
0.76top 25%
GOF
0.74top 25%
LOF
0.2680th %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

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic3
VUS132
Likely Benign10
Benign3
29
Pathogenic
3
Likely Pathogenic
132
VUS
10
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
29
0
29
Likely Pathogenic
0
0
3
0
3
VUS
0
123
9
0
132
Likely Benign
0
6
1
3
10
Benign
0
0
1
2
3
Total0129435177

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

View in ClinVar →

Protein Context — Lollipop Plot

TMTC1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 4 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients