TMEM165

protein-coding

transmembrane protein 165, the group of Solute carrier family 64

Gene summary

This gene encodes a predicted transmembrane protein with a perinuclear Golgi-like distribution in fibroblasts. Mutations in this gene are associated with the autosomal recessive disorder congenital disorder of glycosylation, type IIk. Knockdown of this gene's expression causes decreased sialylation in HEK cells and suggests this gene plays a role in terminal Golgi glycosylation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

MANE transcript

NM_018475.5

Inheritance

ClinVar variants

P:6U:84B:46

Top phenotype

Congenital disorder of glycosylation, type IIk

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr4:55,395,957-55,453,397

External References & Databases

Ensembl (ENSG00000134851)

Transcript & Mutation Effects

hg38 • Region Span ~57.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

TMEM165-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013870

Submitter: Labcorp Genetics (formerly Invitae)

TMEM165-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013870

Submitter: PanelApp Australia

TMEM165-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013870

Submitter: Orphanet

TMEM165-congenital disorder of glycosylationLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013870

Submitter: Ambry Genetics

TMEM165-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013870

Submitter: G2P

TMEM165-congenital disorder of glycosylationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013870

Submitter: ClinGen

*TMEM165* was first reported in relation to autosomal recessive congenital disorder of glycosylation in 2012 (Foulquier et al., PMID: 22683087). Eight unique variants (splice, missense, and nonsense) that have been reported in seven probands in four publications are included in this curation. This gene-disease relationship is also supported by a yeast complementation model (Rosnoblet et al, PMID: 23575229) showing that certain *TMEM165* variants are unable to complement a naturally occurring *TMEM165*-negative strain, and two HEK293 knockout cell models (Foulquier et al., PMID: 22683087 and Morelle et al, PMID: 28323990) showing that lack of *TMEM165* results in glycosylation defects. In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date April 20, 2026 (SOP Version 12).

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IIkAR

Manifestation: Biochemical; Craniofacial; Dental; Dermatologic; Endocrine; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic

Intervention: General

Rationale: Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery

Comments: Hepatic-metabolized agents should be avoided

Refs: 22683087; 23430531

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMEM165 variants in ClinVar

5 Conditions Cataloged

TMEM165-congenital disorder of glycosylationTotal: 134

not specifiedTotal: 44

not providedTotal: 19

TMEM165-related disorderTotal: 6

Aganglionic megacolonTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018475.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				44 clinvar	2 clinvar	46
missense	1 clinvar	2 clinvar	82 clinvar			85
nonsense	1 clinvar	1 clinvar				2
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	2	4	84	44	2	136

Highest pathogenic variant AF is 0.000016108766

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 51 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018475.5	RefSeq	NP_060945.2	6	MANE Select
ENST00000381334.10	Ensembl	ENSP00000370736.5	6	MANE Select
ENST00000506103.2	Ensembl	ENSP00000476621.1	1	Standard
ENST00000506198.5	Ensembl	ENSP00000425449.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tmem165	Danio rerio	Structure: chondrocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

tmem165

Danio rerio

Structure: chondrocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein N-linked glycosylation
cellular calcium ion homeostasis
Golgi calcium ion transport
regulation of lysosomal lumen pH

Cellular Component

lysosomal membrane
Golgi apparatus
endosome membrane
integral component of membrane
early endosome membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000381334
Coding exons: 6
Length: 57441
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125745
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.37	117	167	0.702	0.00000853	2039
Missense (PolyPhen)		34	69.036	0.4925		770
Synonymous	0.469	59	63.8	0.925	0.00000336	687
Loss of Function	2.46	3	12.3	0.244	6.01e-7	168

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May function as a calcium/proton transporter involved in calcium and in lysosomal pH homeostasis. Therefore, it may play an indirect role in protein glycosylation. {ECO:0000269|PubMed:22683087, ECO:0000269|PubMed:23569283}.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.0809
RVIS EVS: -0.3
RVIS percentile EVS: 32.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.231

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium