TMEM237

Chr 2AR

transmembrane protein 237

Also known as: ALS2CR4, JBTS14

NCBI Gene: 65062 ENSG00000155755 UniProt: Q96Q45 OMIM: 614423

The protein is a tetraspanin component of the transition zone in primary cilia and is required for ciliogenesis and involved in WNT signaling. Mutations cause Joubert syndrome 14, a ciliopathy characterized by cerebellar vermis hypoplasia, developmental delay, and brainstem abnormalities. This gene follows autosomal recessive inheritance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a tetraspanin protein that is thought to be involved in WNT signaling. Defects in this gene are a cause of Joubert syndrome-14. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.251 OMIM phenotype

Clinical Summary— TMEM237

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Gene-Disease Validity (ClinGen)

Joubert syndrome 14 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

46 unique Pathogenic / Likely Pathogenic· 262 VUS of 540 total submissions

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GeneReview available — TMEM237

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.25LOEUF

pLI 0.000

Z-score 0.64

OE 0.86 (0.60–1.25)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.09Z-score

OE missense 0.98 (0.87–1.11)

189 obs / 192.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.86 (0.60–1.25)

0≤0.351.4

Missense OE?0.98 (0.87–1.11)

0≤0.61.4

Synonymous OE?0.61

0≤1.21.6

LoF obs/exp: 20 / 23.3Missense obs/exp: 189 / 192.7Syn Z: 2.55

ClinVar Variant Classifications

540 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24

Likely Pathogenic22

VUS262

Likely Benign167

Benign36

Conflicting20

Pathogenic

Likely Pathogenic

262

VUS

167

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	21	0	3	0	24
Likely Pathogenic	22	0	0	0	22
VUS	6	172	79	5	262
Likely Benign	0	1	120	46	167
Benign	0	1	33	2	36
Conflicting	—				20
Total	49	174	235	53	531

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap TMEM237 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →