SEC11A

Chr 15

SEC11 homolog A, signal peptidase complex subunit

Also known as: 1810012E07Rik, SEC11L1, SPC18, SPCS4A, sid2895

NCBI Gene: 23478 ENSG00000140612 UniProt: P67812

The protein is a catalytic component of the signal peptidase complex that cleaves N-terminal signal sequences from nascent proteins as they are translocated into the endoplasmic reticulum. Mutations cause autosomal recessive congenital disorder of glycosylation with severe developmental delay, seizures, and multisystem involvement. The gene shows low constraint to loss-of-function variation, consistent with the recessive inheritance pattern.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the peptidase S26B family. The encoded protein is an 18kDa subunit of the signal peptidase complex and has been linked to cell migration and invasion, gastric cancer and lymph node metastasis. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 8. [provided by RefSeq, Dec 2012]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.99

Clinical Summary— SEC11A

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

14 VUS of 26 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.99LOEUF

pLI 0.002

Z-score 1.59

OE 0.50 (0.28–0.99)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.58Z-score

OE missense 0.55 (0.44–0.69)

53 obs / 96.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.28–0.99)

0≤0.351.4

Missense OE?0.55 (0.44–0.69)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 6 / 11.9Missense obs/exp: 53 / 96.8Syn Z: 0.44

This gene — mechanism propensity

0.7327th %ile

GOF

0.6931th %ile

LOF

0.3647th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

26 submitted variants in ClinVar

ClinVar

Classification Summary

VUS14

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	14	14
Likely Benign	0	0
Benign	0	0
Total	14	14

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 59) ClinVar copy-number / structural variants overlap SEC11A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →