TMEM165

Chr 4AR

transmembrane protein 165

Also known as: CDG2K, FT27, GDT1, SLC64A1, TMPT27, TPARL

NCBI Gene: 55858 ENSG00000134851 UniProt: Q9HC07 OMIM: 614726

This gene encodes a divalent cation:proton antiporter that exchanges calcium or manganese ions for protons across the Golgi membrane, providing essential cofactors to Golgi enzymes involved in glycosylation. Biallelic mutations cause congenital disorder of glycosylation type IIk, an autosomal recessive condition affecting protein glycosylation. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.63), suggesting some tolerance to reduced function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.631 OMIM phenotype

Clinical Summary— TMEM165

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Gene-Disease Validity (ClinGen)

TMEM165-congenital disorder of glycosylation · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 134 VUS of 267 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.63LOEUF

pLI 0.283

Z-score 2.46

OE 0.24 (0.11–0.63)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.37Z-score

OE missense 0.70 (0.60–0.82)

117 obs / 166.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.24 (0.11–0.63)

0≤0.351.4

Missense OE?0.70 (0.60–0.82)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 3 / 12.3Missense obs/exp: 117 / 166.6Syn Z: 0.47

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTMEM165-related congenital disorder of glycosylationLOFAR

This gene — mechanism propensity

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

0.73top 25%

GOF

0.6150th %ile

LOF

0.3261th %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

267 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic2

VUS134

Likely Benign80

Benign23

Conflicting4

Pathogenic

Likely Pathogenic

134

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	1	0	4
Likely Pathogenic	2	0	0	0	2
VUS	1	124	9	0	134
Likely Benign	0	1	36	43	80
Benign	0	0	20	3	23
Conflicting	—				4
Total	4	127	66	46	247

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap TMEM165 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →