SMG6

Chr 17

SMG6 nonsense mediated mRNA decay factor

Also known as: C17orf31, EST1A, SMG-6, hEST1A, hSMG5/7a

NCBI Gene: 23293ENSG00000070366UniProt: Q86US8

This gene encodes a component of the telomerase ribonucleoprotein complex responsible for the replication and maintenance of chromosome ends. The encoded protein also plays a role in the nonsense-mediated mRNA decay (NMD) pathway, providing the endonuclease activity near the premature translation termination codon that is needed to initiate NMD. Alternatively spliced transcript variants encoding distinct protein isoforms have been described. [provided by RefSeq, Feb 2014]

344
ClinVar variants
68
Pathogenic / LP
0.98
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SMG6
⚡
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
68 Pathogenic / Likely Pathogenic· 253 VUS of 344 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 6.10
OE 0.18 (0.12–0.30)
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.
0.18Z-score
OE missense 0.98 (0.93–1.04)
820 obs / 834.5 exp
Tolerant

Mild missense constraint

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.0.18 (0.12–0.30)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.93–1.04)
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.1.16
0≤1.21.6
LoF obs/exp: 12 / 65.1Missense obs/exp: 820 / 834.5Syn Z: -2.28

ClinVar Variant Classifications

344 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic62
Likely Pathogenic6
VUS253
Likely Benign17
Benign6
62
Pathogenic
6
Likely Pathogenic
253
VUS
17
Likely Benign
6
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
62
0
62
Likely Pathogenic
0
0
6
0
6
VUS
0
234
18
1
253
Likely Benign
0
10
2
5
17
Benign
0
4
1
1
6
Total0248897344

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

View in ClinVar →

Protein Context — Lollipop Plot

SMG6 · 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
Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.
Eicher JD et al.·Am J Hum Genet
2016Meta-analysis
Chromatin Accessibility of Human Mitral Valves and Functional Assessment of MVP Risk Loci.
Kyryachenko S et al.·Circ Res
2021Functional
An epigenome-wide DNA methylation study of patients with COVID-19.
Zhou S et al.·Ann Hum Genet
2021Cohort
A genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine.
Guo Y et al.·Nat Commun
2020
Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.
Lindström S et al.·Blood
2019
Genetic Variants Related to TGF-β Signaling Pathway Modulate Risk of Meniscus Injury: A Multiancestry Genome-wide Association Study.
Umesh A et al.·Clin Orthop Relat Res
2026Meta-analysis
Genetic polymorphism predicting Methotrexate efficacy in Chinese patients with psoriasis vulgaris.
Kuang YH et al.·J Dermatol Sci
2019Cohort
A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses.
Baranski TJ et al.·PLoS Genet
2018Functional
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