SEL1L

Chr 14AR

SEL1L adaptor subunit of SYVN1 ubiquitin ligase

Also known as: Hrd3, NEDGSAF, NEDHGFA, PRO1063, SEL1-LIKE, SEL1L1

NCBI Gene: 6400ENSG00000071537UniProt: Q9UBV2

The protein encoded by this gene is part of a protein complex required for the retrotranslocation or dislocation of misfolded proteins from the endoplasmic reticulum lumen to the cytosol, where they are degraded by the proteasome in a ubiquitin-dependent manner. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

Primary Disease Associations & Inheritance

?Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic faciesMIM #621067
AR
Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemiaMIM #621068
AR
130
ClinVar variants
5
Pathogenic / LP
0.98
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SEL1L
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
5 Pathogenic / Likely Pathogenic· 74 VUS of 130 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.30LOEUF
pLI 0.982
Z-score 5.32
OE 0.17 (0.10–0.30)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.41Z-score
OE missense 0.67 (0.61–0.74)
289 obs / 429.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.17 (0.10–0.30)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.61–0.74)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 8 / 47.6Missense obs/exp: 289 / 429.9Syn Z: 0.16

ClinVar Variant Classifications

130 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic1
VUS74
4
Pathogenic
1
Likely Pathogenic
74
VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
3
0
4
Likely Pathogenic
0
0
1
0
1
VUS
0
71
2
1
74
Likely Benign
0
0
0
0
0
Benign
0
0
0
0
0
Total0726179

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

View in ClinVar →

Protein Context — Lollipop Plot

SEL1L · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies

MIM #621067

Molecular basis of disorder known

Autosomal recessive

Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia

MIM #621068

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD.
Song Z et al.·Nat Commun
2024
Regulation of leptin signaling and diet-induced obesity by SEL1L-HRD1 ER-associated degradation in POMC expressing neurons.
Mao H et al.·Nat Commun
2024
Biallelic Cys141Tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death.
Weis D et al.·J Clin Invest
2024
Natural SEL1L variants rescue a model of NGLY1 deficiency and modify ERAD function and proteasome sensitivity.
Tu'ifua TK et al.·PLoS Genet
2025Functional
Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders.
Wang HH et al.·J Clin Invest
2024
HSPA12B Protects Against Age-Related Endothelial Cell Senescence by Regulating STING Degradation.
Li T et al.·Aging Cell
2025
Hypomorphic human SEL1L and HRD1 variants uncouple multilayered ER-associated degradation machinery.
Umphred-Wilson K et al.·J Clin Invest
2024
SEL1L plays a major role in human malignant gliomas.
Mellai M et al.·J Pathol Clin Res
2020
SEL1L expression in pancreatic adenocarcinoma parallels SMAD4 expression and delays tumor growth in vitro and in vivo.
Cattaneo M et al.·Oncogene
2003
Structural basis and pathological implications of the dimeric OS9-SEL1L-HRD1 ERAD Core Complex.
Lin LL et al.·Nat Commun
2026
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools