SMG1

Chr 16

SMG1 nonsense mediated mRNA decay associated PI3K related kinase

Also known as: 61E3.4, ATX, LIP

NCBI Gene: 23049ENSG00000157106UniProt: Q96Q15

This gene encodes a protein involved in nonsense-mediated mRNA decay (NMD) as part of the mRNA surveillance complex. The protein has kinase activity and is thought to function in NMD by phosphorylating the regulator of nonsense transcripts 1 protein. Alternatively spliced transcript variants have been described, but their full-length nature has yet to be determined. [provided by RefSeq, Mar 2013]

114
ClinVar variants
14
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SMG1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 30 VUS of 114 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.05LOEUF
pLI 1.000
Z-score 11.88
OE 0.02 (0.01–0.05)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
3.30Z-score
OE missense 0.78 (0.74–0.81)
1372 obs / 1761.5 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.02 (0.01–0.05)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.78 (0.74–0.81)
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.1.14
0≤1.21.6
LoF obs/exp: 4 / 172.4Missense obs/exp: 1372 / 1761.5Syn Z: -2.76

ClinVar Variant Classifications

114 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14
VUS30
Likely Benign8
Benign4
14
Pathogenic
30
VUS
8
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
14
0
14
Likely Pathogenic
0
0
0
0
0
VUS
0
24
5
1
30
Likely Benign
0
2
1
5
8
Benign
0
2
0
2
4
Total02820856

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

View in ClinVar →

Protein Context — Lollipop Plot

SMG1 · 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
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Effects of heterozygous SMG1 mutations on nonsense-mediated mRNA decay in human pluripotent stem cell model.
Lee C et al.·Mol Cells
2025Functional
SMG1, a nonsense-mediated mRNA decay (NMD) regulator, as a candidate therapeutic target in multiple myeloma.
Leeksma AC et al.·Mol Oncol
2023
Targeting the estrogen receptor alpha (ERα)-mediated circ-SMG1.72/miR-141-3p/Gelsolin signaling to better suppress the HCC cell invasion.
Xiao Y et al.·Oncogene
2020
MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma.
Mai S et al.·Cell Death Dis
2019
SMG8/SMG9 Heterodimer Loss Modulates SMG1 Kinase to Drive ATR Inhibitor Resistance.
Llorca-Cardenosa MJ et al.·Cancer Res
2022
Unveiling the Pathogenic Role of Novel CPLANE1 Compound Heterozygous Variants in Joubert Syndrome: Insights Into mRNA Stability and NMD Pathway.
Hong Z et al.·J Cell Mol Med
2025
Compound C inhibits nonsense-mediated RNA decay independently of AMPK.
Cheruiyot A et al.·PLoS One
2018
A region-based gene association study combined with a leave-one-out sensitivity analysis identifies SMG1 as a pancreatic cancer susceptibility gene.
Wong C et al.·PLoS Genet
2019
LncRNA MAGI2-AS3 inhibits hepatocellular carcinoma cell proliferation and migration by targeting the miR-374b-5p/SMG1 signaling pathway.
Yin Z et al.·J Cell Physiol
2019
Biological and clinical significance of epigenetic silencing of MARVELD1 gene in lung cancer.
Shi M et al.·Sci Rep
2014
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