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…

Primary Disease Associations & Inheritance

Joubert syndrome 2MIM #608091

Meckel syndrome 2MIM #603194

Retinitis pigmentosa 98MIM #620996

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · ciliopathy · AR · ClinGen 2024

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.37

LOEUF

Multiple*

Mechanism· predicted

📖

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

Background carrier burden — how many people carry a rare variant somewhere in TMEM216?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

166 rare PASS variants

Rare truncating (LoF)

1 in 1,500

53 rare PASS variants

Rare synonymous (reference)

1 in 390

68 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TMEM216. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 230	1 in 1,600
South Asian	~43k	1 in 450	1 in 5,200
Remaining (unassigned)	~30k	1 in 180	1 in 1,400
European (Finnish)	~27k	1 in 3,500	none seen
Admixed American	~22k	1 in 260	1 in 540
African / African American	~21k	1 in 270	1 in 1,800
East Asian	~20k	1 in 220	1 in 930
Ashkenazi Jewish	~13k	≈ 1 in 6,500	1 in 1,700
Middle Eastern	~2,884	1 in 410	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓