SEC63

Chr 6AD

SEC63 protein translocation regulator

Also known as: DNAJC23, ERdj2, PCLD2, PRO2507, SEC63L

NCBI Gene: 11231 ENSG00000025796 UniProt: Q9UGP8 OMIM: 608648

The SEC63 protein mediates cotranslational and post-translational transport of precursor polypeptides across the endoplasmic reticulum membrane as part of the SEC61-SEC62-SEC63 translocon complex. Mutations cause autosomal recessive polycystic liver disease and congenital disorder of glycosylation type IIp, affecting hepatic and metabolic systems. The gene is highly constrained against loss-of-function variants (LOEUF 0.57), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, UniProt

The Sec61 complex is the central component of the protein translocation apparatus of the endoplasmic reticulum (ER) membrane. The protein encoded by this gene and SEC62 protein are found to be associated with ribosome-free SEC61 complex. It is speculated that Sec61-Sec62-Sec63 may perform post-translational protein translocation into the ER. The Sec61-Sec62-Sec63 complex might also perform the backward transport of ER proteins that are subject to the ubiquitin-proteasome-dependent degradation pathway. The encoded protein is an integral membrane protein located in the rough ER. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Polycystic liver disease 2MIM #617004

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · polycystic liver disease 2 · AD · ClinGen 2020

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.57

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.57LOEUF

pLI 0.000

Z-score 4.07

OE 0.40 (0.28–0.57)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.20Z-score

OE missense 0.69 (0.62–0.76)

275 obs / 398.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.40 (0.28–0.57)

0≤0.351.4

Missense OE?0.69 (0.62–0.76)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 21 / 53.0Missense obs/exp: 275 / 398.6Syn Z: -0.06

Background carrier burden — how many people carry a rare variant somewhere in SEC63?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

720 rare PASS variants

Rare truncating (LoF)

1 in 980

112 rare PASS variants

Rare synonymous (reference)

1 in 220

305 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SEC63. 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 160	1 in 1,500
South Asian	~43k	1 in 110	1 in 940
Remaining (unassigned)	~30k	1 in 150	1 in 1,900
European (Finnish)	~27k	1 in 260	1 in 990
Admixed American	~22k	1 in 130	1 in 370
African / African American	~21k	1 in 150	1 in 440
East Asian	~20k	1 in 140	1 in 3,900
Ashkenazi Jewish	~13k	1 in 860	1 in 1,800
Middle Eastern	~2,884	1 in 120	≈ 1 in 1,400

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): 13 of 21 coding exons well covered in gnomAD exomes; exons 2, 3, 7, 8, 13 and 3 more marginal. Genomes: 20 of 21 (exon 19 below).? see exons ↓