TMCO1

Chr 1AR

transmembrane and coiled-coil domains 1

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

NCBI Gene: 54499 ENSG00000143183 UniProt: Q9UM00 OMIM: 614123

The TMCO1 protein functions as an endoplasmic reticulum calcium-selective channel that maintains ER calcium homeostasis and serves as a component of the multi-pass translocon complex for membrane protein insertion. Biallelic mutations cause craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development with autosomal recessive inheritance. This gene shows extremely strong constraint against loss-of-function variants (pLI ~1), indicating that heterozygous loss-of-function is likely incompatible with normal development.

GeneReviews OMIM ResearchSummary from OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1MIM #213980

UniProtGlaucoma, primary open angle

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.36

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — TMCO1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

1.03Z-score

OE missense 0.74 (0.63–0.88)

96 obs / 128.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.89 (0.59–1.36)

0≤0.351.4

Missense OE?0.74 (0.63–0.88)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 15 / 16.9Missense obs/exp: 96 / 128.9Syn Z: -0.07

Background carrier burden — how many people carry a rare variant somewhere in TMCO1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

304 rare PASS variants

Rare truncating (LoF)

1 in 970

77 rare PASS variants

Rare synonymous (reference)

1 in 810

134 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TMCO1. 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 380	1 in 910
South Asian	~43k	1 in 210	1 in 2,400
Remaining (unassigned)	~30k	1 in 150	1 in 890
European (Finnish)	~27k	1 in 750	1 in 5,300
Admixed American	~22k	1 in 170	1 in 920
African / African American	~21k	1 in 110	1 in 1,200
East Asian	~20k	1 in 340	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 650	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 290	≈ 1 in 1,400

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): All 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓