TMEM138

Chr 11AR

transmembrane protein 138

Also known as: HSPC196

NCBI Gene: 51524 ENSG00000149483 UniProt: Q9NPI0 OMIM: 614459

This gene encodes a multi-pass transmembrane protein required for ciliogenesis, the formation of primary cilia that are essential for cellular signaling pathways. Mutations cause Joubert syndrome 16, an autosomal recessive neurodevelopmental disorder characterized by cerebellar vermis hypoplasia, developmental delay, and distinctive brain malformations. The gene has relatively low constraint against loss-of-function variants (pLI 0.05), consistent with its recessive inheritance pattern where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a multi-pass transmembrane protein. Reduced expression of this gene in mouse fibroblasts causes short cilia and failure of ciliogenesis. Expression of this gene is tightly coordinated with expression of the neighboring gene TMEM216. Mutations in this gene are associated with the autosomal recessive neurodevelopmental disorder Joubert Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.111 OMIM phenotype

Clinical Summary— TMEM138

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Gene-Disease Validity (ClinGen)

ciliopathy · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.05) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

21 unique Pathogenic / Likely Pathogenic· 90 VUS of 198 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TMEM138

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?

1.11LOEUF

pLI 0.047

Z-score 1.40

OE 0.43 (0.19–1.11)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.47Z-score

OE missense 0.86 (0.71–1.04)

75 obs / 87.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.19–1.11)

0≤0.351.4

Missense OE?0.86 (0.71–1.04)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 3 / 7.0Missense obs/exp: 75 / 87.4Syn Z: -0.16

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongTMEM138-related Joubert syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.80top 25%

GOF

0.78top 25%

LOF

0.2190th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

198 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic13

VUS90

Likely Benign63

Benign9

Conflicting10

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	1	2	0	8
Likely Pathogenic	8	3	2	0	13
VUS	6	64	20	0	90
Likely Benign	0	1	36	26	63
Benign	0	0	8	1	9
Conflicting	—				10
Total	19	69	68	27	193

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap TMEM138 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →