TMEM138

Chr 11AR

transmembrane protein 138

Also known as: HSPC196

NCBI Gene: 51524ENSG00000149483UniProt: Q9NPI0

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]

Primary Disease Associations & Inheritance

Joubert syndrome 16MIM #614465
AR
205
ClinVar variants
31
Pathogenic / LP
0.05
pLI score
0
Active trials
Clinical Summary— TMEM138
🧬
Gene-Disease Validity (ClinGen)
ciliopathy · ARModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.05) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
31 Pathogenic / Likely Pathogenic· 93 VUS of 205 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.
1.11LOEUF
pLI 0.047
Z-score 1.40
OE 0.43 (0.19–1.11)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?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.
0.47Z-score
OE missense 0.86 (0.71–1.04)
75 obs / 87.4 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.0.43 (0.19–1.11)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.71–1.04)
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.1.04
0≤1.21.6
LoF obs/exp: 3 / 7.0Missense obs/exp: 75 / 87.4Syn Z: -0.16

ClinVar Variant Classifications

205 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14
Likely Pathogenic17
VUS93
Likely Benign62
Benign9
Conflicting10
14
Pathogenic
17
Likely Pathogenic
93
VUS
62
Likely Benign
9
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
12
0
14
Likely Pathogenic
8
3
6
0
17
VUS
4
63
26
0
93
Likely Benign
0
1
35
26
62
Benign
0
0
8
1
9
Conflicting
—10
Total13688727205

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

View in ClinVar →

Protein Context — Lollipop Plot

TMEM138 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TMEM138-related Joubert syndrome

strong
ARLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Joubert syndrome 16

MIM #614465

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — TMEM138
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
TMEM138: From Biological Functions to Diseases.
Shi Q et al.·Physiol Res
2025Review
Loci associated with skin pigmentation identified in African populations.
Crawford NG et al.·Science
2017
MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone.
Li C et al.·PLoS Biol
2016
Molecular genetic analysis of 30 families with Joubert syndrome.
Suzuki T et al.·Clin Genet
2016
A case series of joubert syndrome evaluated with whole exome sequencing and the utility of optical genome mapping in the diagnosis.
Kiraz A et al.·Neurogenetics
2025Cohort
The diagnostic yield of whole exome sequencing as a first approach in consanguineous Omani renal ciliopathy syndrome patients.
Al Alawi I et al.·F1000Res
2021Cohort
Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes.
Bruel AL et al.·J Med Genet
2017Review
Meckel Gruber and Joubert Syndrome Diagnosed Prenatally: Allelism between the Two Ciliopathies, Complexities of Mutation Types and Digenic Inheritance.
Srivastava S et al.·Fetal Pediatr Pathol
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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