TMCO1

Chr 1AR

transmembrane and coiled-coil domains 1

Also known as: CFSMR1, HP10122, PCIA3, PNAS-136, TMCC4

NCBI Gene: 54499ENSG00000143183UniProt: Q9UM00

This locus encodes a transmembrane protein. Mutations at this locus have been associated with craniofacial dysmorphism, skeletal anomalies, and cognitive disability. Mutations at this locus have also been associated with open angle glaucoma blindness. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]

Primary Disease Associations & Inheritance

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1MIM #213980
AR
UniProtGlaucoma, primary open angle
103
ClinVar variants
35
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TMCO1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
35 Pathogenic / Likely Pathogenic· 28 VUS of 103 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.36LOEUF
pLI 0.000
Z-score 0.44
OE 0.89 (0.59–1.36)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.03Z-score
OE missense 0.74 (0.63–0.88)
96 obs / 128.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.89 (0.59–1.36)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.74 (0.63–0.88)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 15 / 16.9Missense obs/exp: 96 / 128.9Syn Z: -0.07

ClinVar Variant Classifications

103 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26
Likely Pathogenic9
VUS28
Likely Benign25
Benign15
26
Pathogenic
9
Likely Pathogenic
28
VUS
25
Likely Benign
15
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
24
0
26
Likely Pathogenic
5
1
3
0
9
VUS
1
24
3
0
28
Likely Benign
0
1
16
8
25
Benign
0
1
13
1
15
Total728599103

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

View in ClinVar →

Protein Context — Lollipop Plot

TMCO1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TMCO1-related craniofacial dysmorphism, skeletal anomalies, and intellectual developmental disorder syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1

MIM #213980

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — TMCO1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 in two new patients with the same homozygous TMCO1 variant and review of the literature.
Abdelrazek IM et al.·Eur J Med Genet
2023Review
TMCO1 regulates cell proliferation, metastasis and EMT signaling through CALR, promoting ovarian cancer progression and cisplatin resistance.
Sun G et al.·Cell Mol Biol (Noisy-le-grand)
2024
Cerebrofaciothoracic dysplasia: Four new patients with a recurrent TMCO1 pathogenic variant.
Michael Yates T et al.·Am J Med Genet A
2019Cohort
TMCO1 Is an ER Ca(2+) Load-Activated Ca(2+) Channel.
Wang QC et al.·Cell
2016
Ca(2+) homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling.
Yang KY et al.·Cell Death Dis
2022
Association of genetic variants in the TMCO1 gene with clinical parameters related to glaucoma and characterization of the protein in the eye.
Sharma S et al.·Invest Ophthalmol Vis Sci
2012
A novel biallelic loss-of-function mutation in TMCO1 gene confirming and expanding the phenotype spectrum of cerebro-facio-thoracic dysplasia.
Sharkia R et al.·Am J Med Genet A
2019Case report
Glaucoma Risk Alleles in the Ocular Hypertension Treatment Study.
Scheetz TE et al.·Ophthalmology
2016
Whole-exome sequencing links TMCO1 defect syndrome with cerebro-facio-thoracic dysplasia.
Pehlivan D et al.·Eur J Hum Genet
2014Case report
Genetics of primary open-angle glaucoma and its endophenotypes.
Sakurada Y et al.·Prog Brain Res
2020Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
[Elevated TMCO1 expression in gastric cancer is associated poor prognosis and promotes malignant phenotypes of tumor cells by inhibiting apoptosis].
Song B et al.·Nan Fang Yi Ke Da Xue Xue Bao
2025
TMCO1 as an Endoplasmic Reticulum Calcium Load-Activated Channel: Mechanisms and Disease Implications.
Wang J et al.·Biomolecules
2025🔓 Open AccessFunctional
TMCO1, as a potential biomarker of prognosis and immunotherapy response, regulates head and neck squamous cell carcinoma proliferation and migration.
Li T et al.·Discov Oncol
2025🔓 Open Access
Tmco1-Deficient Mice Exhibit a High Incidence of Otitis Media Associated with Impaired Bone Homeostasis in the Middle Ear.
Dong Y et al.·Am J Pathol
2025
TMCO1 regulates energy metabolism and mitochondrial function of hepatocellular carcinoma cells through TOMM20, affecting the growth of subcutaneous graft tumors and infiltration of CAFs.
Wang G et al.·Biochem Cell Biol
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools