TMEM216

Chr 11AR

transmembrane protein 216

Also known as: HSPC244, RP98

NCBI Gene: 51259ENSG00000187049UniProt: Q9P0N5

This locus encodes a transmembrane domain-containing protein. Mutations at this locus have been associated with Meckel-Gruber Syndrome Type 2, and Joubert Syndrome 2, also known as Cerebello-oculorenal Syndrome 2. [provided by RefSeq, Aug 2010]

Primary Disease Associations & Inheritance

Joubert syndrome 2MIM #608091
AR
Meckel syndrome 2MIM #603194
AR
Retinitis pigmentosa 98MIM #620996
AR
337
ClinVar variants
65
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TMEM216
🧬
Gene-Disease Validity (ClinGen)
ciliopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
65 Pathogenic / Likely Pathogenic· 113 VUS of 337 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.
1.37LOEUF
pLI 0.002
Z-score 0.88
OE 0.66 (0.34–1.37)
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.
0.49Z-score
OE missense 0.84 (0.69–1.04)
66 obs / 78.2 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.0.66 (0.34–1.37)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.84 (0.69–1.04)
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.0.78
0≤1.21.6
LoF obs/exp: 5 / 7.6Missense obs/exp: 66 / 78.2Syn Z: 1.00

ClinVar Variant Classifications

337 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic40
VUS113
Likely Benign130
Benign10
Conflicting19
25
Pathogenic
40
Likely Pathogenic
113
VUS
130
Likely Benign
10
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
1
14
0
25
Likely Pathogenic
27
3
10
0
40
VUS
6
67
35
5
113
Likely Benign
1
1
65
63
130
Benign
3
0
6
1
10
Conflicting
—19
Total477213069337

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

View in ClinVar →

Protein Context — Lollipop Plot

TMEM216 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TMEM216-related Joubert syndrome

strong
ARUndeterminedAltered Gene Product Structure
Dev. DisordersEye
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Joubert syndrome 2

MIM #608091

Molecular basis of disorder known

Autosomal recessive

Meckel syndrome 2

MIM #603194

Molecular basis of disorder known

Autosomal recessive

Retinitis pigmentosa 98

MIM #620996

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — TMEM216
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression.
Malka S et al.·Am J Hum Genet
2024
TMEM216 Deletion Causes Mislocalization of Cone Opsin and Rhodopsin and Photoreceptor Degeneration in Zebrafish.
Liu Y et al.·Invest Ophthalmol Vis Sci
2020Functional
Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes.
Valente EM et al.·Nat Genet
2010
Recurrent, founder and hypomorphic variants contribute to the genetic landscape of Joubert syndrome.
Serpieri V et al.·J Med Genet
2023
Molecular genetics and pathogenic mechanisms for the severe ciliopathies: insights into neurodevelopment and pathogenesis of neural tube defects.
Logan CV et al.·Mol Neurobiol
2011Review
Interpreting the pathogenicity of Joubert syndrome missense variants in Caenorhabditis elegans.
Lange KI et al.·Dis Model Mech
2021
Thumb duplication: molecular analysis of different clinical types.
Kyriazis Z et al.·Eur J Orthop Surg Traumatol
2019
Mutations in DDX59 implicate RNA helicase in the pathogenesis of orofaciodigital syndrome.
Shamseldin HE et al.·Am J Hum Genet
2013
Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy.
Otto EA et al.·J Med Genet
2011
B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis.
Hopp K et al.·Hum Mol Genet
2011
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