TMEM231

Chr 16AR

transmembrane protein 231

Also known as: ALYE870, JBTS20, MKS11, PRO1886

NCBI Gene: 79583 ENSG00000205084 UniProt: Q9H6L2 OMIM: 614949

This gene encodes a transmembrane component of the tectonic-like complex that acts as a barrier preventing diffusion of transmembrane proteins between the cilia and plasma membranes, and is required for ciliogenesis and sonic hedgehog signaling. Mutations cause Joubert syndrome and Meckel syndrome, both severe ciliopathies affecting the brain, kidneys, liver, and other organ systems. The gene follows autosomal recessive inheritance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a transmembrane protein, which is a component of the B9 complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. Mutations in this gene cause Joubert syndrome (JBTS). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Joubert syndrome 20MIM #614970

Meckel syndrome 11MIM #615397

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · ciliopathy · AR · ClinGen 2022

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

1.21

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — TMEM231

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?

1.21LOEUF

pLI 0.000

Z-score 0.93

OE 0.75 (0.48–1.21)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.41Z-score

OE missense 1.08 (0.97–1.22)

201 obs / 185.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.75 (0.48–1.21)

0≤0.351.4

Missense OE?1.08 (0.97–1.22)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 12 / 16.0Missense obs/exp: 201 / 185.3Syn Z: -0.68

Background carrier burden — how many people carry a rare variant somewhere in TMEM231?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 79

599 rare PASS variants

Rare truncating (LoF)

1 in 720

110 rare PASS variants

Rare synonymous (reference)

1 in 230

176 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TMEM231. 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 87	1 in 670
South Asian	~43k	1 in 88	1 in 800
Remaining (unassigned)	~30k	1 in 58	1 in 660
European (Finnish)	~27k	1 in 270	1 in 1,700
Admixed American	~22k	1 in 63	1 in 1,100
African / African American	~21k	1 in 77	1 in 900
East Asian	~20k	1 in 67	1 in 570
Ashkenazi Jewish	~13k	1 in 150	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 62	none seen

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): 4 of 7 coding exons well covered in gnomAD exomes; exons 1, 3, 4 marginal. Genomes: 5 of 7 (exons 3, 4 below).? see exons ↓