TM6SF2

protein-coding

transmembrane 6 superfamily member 2

Gene summary

Enables identical protein binding activity. Involved in regulation of lipid metabolic process. Located in endoplasmic reticulum membrane and endoplasmic reticulum-Golgi intermediate compartment membrane. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_001001524.3

Inheritance

—

ClinVar variants

U:59B:7

Top phenotype

TM6SF2-related condition

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr19:19,264,364-19,273,391

External References & Databases

Ensembl (ENSG00000213996)

Transcript & Mutation Effects

hg38 • Region Span ~9.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TM6SF2 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 57

not providedTotal: 6

TM6SF2-related conditionTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001001524.3. 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				2 clinvar		2
missense			59 clinvar	4 clinvar	1 clinvar	64
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	59	6	1	66

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001001524.3	RefSeq	NP_001001524.2	10	MANE Select
ENST00000389363.5	Ensembl	ENSP00000374014.2	10	MANE Select
ENST00000864048.1	Ensembl	ENSP00000534107.1	7	Standard
ENST00000864048.2	Ensembl	ENSP00000534107.1	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tm6sf2	Danio rerio	Structure: enterocyte Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

tm6sf2

Danio rerio

Structure: enterocyte

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

lipid metabolic process
regulation of lipid metabolic process

Molecular Function

molecular_function
protein binding

Cellular Component

endoplasmic reticulum membrane
integral component of membrane
endoplasmic reticulum-Golgi intermediate compartment membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000389363
Coding exons: 10
Length: 9028
Individuals with no LoFs: 124773
Homozygous LoFs: 0
Heterozygous LoFs: 35
Defined: 124808
p: 0.000140

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.781	186	218	0.851	0.0000127	2396
Missense (PolyPhen)		58	75.165	0.77164		867
Synonymous	-0.0595	95	94.3	1.01	0.00000588	763
Loss of Function	1.82	10	18.4	0.543	7.84e-7	215

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00039	0.00039	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00048	0.00033	rare
Finnish	0.000051	0.000046	rare
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.00014	0.00013	rare
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content (PubMed:24531328, PubMed:24927523). May function as sterol isomerase (PubMed:25566323). {ECO:0000269|PubMed:24531328, ECO:0000269|PubMed:24927523, ECO:0000303|PubMed:25566323}.;

Intolerance Scores

LoFtool: 0.788
RVIS EVS: 0.37
RVIS percentile EVS: 75.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.335

Gene Damage Prediction

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