TMEM216

Chr 11AR

transmembrane protein 216

Also known as: HSPC244, RP98

NCBI Gene: 51259 ENSG00000187049 UniProt: Q9P0N5 OMIM: 613277

The encoded transmembrane protein is essential for primary ciliogenesis and embryonic development, facilitating Hedgehog signaling pathway activation and ensuring proper photoreceptor outer segment development. Autosomal recessive mutations cause Joubert syndrome 2, Meckel syndrome 2, and retinitis pigmentosa 98, representing a spectrum of ciliopathy disorders affecting the brain, kidneys, and retina. These conditions typically present in infancy to early childhood with characteristic cerebellar malformation (molar tooth sign), cystic kidney disease, and progressive vision loss.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.373 OMIM phenotypes

Clinical Summary— TMEM216

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Gene-Disease Validity (ClinGen)

ciliopathy · 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

57 unique Pathogenic / Likely Pathogenic· 109 VUS of 332 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TMEM216

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?

1.37LOEUF

pLI 0.002

Z-score 0.88

OE 0.66 (0.34–1.37)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.49Z-score

OE missense 0.84 (0.69–1.04)

66 obs / 78.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.66 (0.34–1.37)

0≤0.351.4

Missense OE?0.84 (0.69–1.04)

0≤0.61.4

Synonymous OE?0.78

0≤1.21.6

LoF obs/exp: 5 / 7.6Missense obs/exp: 66 / 78.2Syn Z: 1.00

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongTMEM216-related Joubert syndromeOTHERAR

This gene — mechanism propensity

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

0.75top 25%

GOF

0.81top 10%

LOF

0.2288th %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

332 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19

Likely Pathogenic38

VUS109

Likely Benign130

Benign10

Conflicting19

Pathogenic

Likely Pathogenic

109

VUS

130

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	15	1	3	0	19
Likely Pathogenic	34	3	1	0	38
VUS	6	69	29	5	109
Likely Benign	1	1	65	63	130
Benign	3	0	6	1	10
Conflicting	—				19
Total	59	74	104	69	325

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 TMEM216 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →