SIL1

Chr 5AR

SIL1 nucleotide exchange factor

Also known as: BAP, MSS, ULG5

NCBI Gene: 64374 ENSG00000120725 OMIM: 608005

The protein functions as a nucleotide exchange factor for the ER luminal chaperone HSPA5 and is required for protein translocation and folding in the endoplasmic reticulum. Mutations cause Marinesco-Sjögren syndrome, inherited in an autosomal recessive pattern. The pathogenic mechanism appears to be dominant negative.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a resident endoplasmic reticulum (ER), N-linked glycoprotein with an N-terminal ER targeting sequence, 2 putative N-glycosylation sites, and a C-terminal ER retention signal. This protein functions as a nucleotide exchange factor for another unfolded protein response protein. Mutations in this gene have been associated with Marinesco-Sjogren syndrome. Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.641 OMIM phenotype

Clinical Summary— SIL1

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Gene-Disease Validity (ClinGen)

Marinesco-Sjogren syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

38 unique Pathogenic / Likely Pathogenic· 188 VUS of 427 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SIL1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.012

Z-score 2.79

OE 0.34 (0.19–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.47Z-score

OE missense 0.92 (0.82–1.02)

234 obs / 255.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.19–0.64)

0≤0.351.4

Missense OE?0.92 (0.82–1.02)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 7 / 20.7Missense obs/exp: 234 / 255.2Syn Z: -0.64

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSIL1-related Marinesco-Sjoegren syndromeLOFAR

This gene — mechanism propensity

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

0.6937th %ile

GOF

0.6540th %ile

LOF

0.2385th %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

427 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27

Likely Pathogenic11

VUS188

Likely Benign145

Benign20

Conflicting25

Pathogenic

Likely Pathogenic

188

VUS

145

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	23	1	3	0	27
Likely Pathogenic	8	0	3	0	11
VUS	1	164	17	6	188
Likely Benign	0	7	49	89	145
Benign	0	1	16	3	20
Conflicting	—				25
Total	32	173	88	98	416

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap SIL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →