SIM1

Chr 6

SIM bHLH transcription factor 1

Also known as: bHLHe14

NCBI Gene: 6492ENSG00000112246UniProt: P81133

SIM1 and SIM2 genes are Drosophila single-minded (sim) gene homologs. SIM1 transcript was detected only in fetal kidney out of various adult and fetal tissues tested. Since the sim gene plays an important role in Drosophila development and has peak levels of expression during the period of neurogenesis,it was proposed that the human SIM gene is a candidate for involvement in certain dysmorphic features (particularly the facial and skull characteristics), abnormalities of brain development, and/or cognitive disability of Down syndrome. [provided by RefSeq, Jul 2008]

398
ClinVar variants
16
Pathogenic / LP
1.00
pLI score· haploinsufficient
4
Active trials
Clinical Summary— SIM1
⚡
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
16 Pathogenic / Likely Pathogenic· 269 VUS of 398 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

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.
0.25LOEUF
pLI 0.998
Z-score 4.96
OE 0.11 (0.05–0.25)
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.
0.71Z-score
OE missense 0.90 (0.83–0.98)
405 obs / 447.6 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.0.11 (0.05–0.25)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.90 (0.83–0.98)
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.1.03
0≤1.21.6
LoF obs/exp: 4 / 36.2Missense obs/exp: 405 / 447.6Syn Z: -0.31

ClinVar Variant Classifications

398 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic5
VUS269
Likely Benign92
Benign17
Conflicting4
11
Pathogenic
5
Likely Pathogenic
269
VUS
92
Likely Benign
17
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
9
0
11
Likely Pathogenic
2
0
3
0
5
VUS
5
238
20
6
269
Likely Benign
0
7
13
72
92
Benign
0
0
15
2
17
Conflicting
—4
Total92456080398

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

View in ClinVar →

Protein Context — Lollipop Plot

SIM1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SIM1-related severe obesity with neurobehavioural features

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
CD36-mediated endocytosis of proteolysis-targeting chimeras.
Wang Z et al.·Cell
2025
Genetics of Obesity in Humans: A Clinical Review.
Mahmoud R et al.·Int J Mol Sci
2022Review
Metabolic Effects of Oxytocin.
McCormack SE et al.·Endocr Rev
2020Review
Updated penetrance estimates for recurrent copy number variants - an improved definition and formula.
Goh S et al.·Eur J Hum Genet
2026
Variant reclassification over time decreases the level of diagnostic uncertainty in monogenic obesity: Experience from two centres.
Morandi A et al.·Pediatr Obes
2024
A Comprehensive Review of Syndromic Forms of Obesity: Genetic Etiology, Clinical Features and Molecular Diagnosis.
Carvalho LML et al.·Curr Obes Rep
2024Review
Effects of Rare Coding Variants in Severe Early-Onset Obesity Genes in the Population-Based UK Biobank Study.
Jia RY et al.·J Clin Endocrinol Metab
2025
Neuropathologic research strategies in holoprosencephaly.
Sarnat HB et al.·J Child Neurol
2001Review
Mutation screen of the SIM1 gene in pediatric patients with early-onset obesity.
Zegers D et al.·Int J Obes (Lond)
2014Cohort
Rare variants in single-minded 1 (SIM1) are associated with severe obesity.
Ramachandrappa S et al.·J Clin Invest
2013
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Novel SIM1 Variants Expanding the Spectrum of SIM1-Related Obesity.
Mohammed I et al.·Int J Mol Sci
2026🔓 Open Access
Effects of targeted deletion of a 284 bp avian-specific highly conserved element within the Sim1 gene on flight feather development in chickens.
Kinoshita K et al.·Zool Res
2025🔓 Open Access
Growth hormone receptor in VGLUT2 or Sim1 cells regulates glycemia and insulin sensitivity.
Tavares MR et al.·Proc Natl Acad Sci U S A
2024🔓 Open Access
Melanocortin 4 receptor signaling in Sim1 neurons permits sexual receptivity in female mice.
Semple EA et al.·Front Endocrinol (Lausanne)
2023🔓 Open Access
Distinct Subdivisions in the Transition Between Telencephalon and Hypothalamus Produce Otp and Sim1 Cells for the Extended Amygdala in Sauropsids.
Metwalli AH et al.·Front Neuroanat
2022🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Obesity

Intensive Weight Loss Intervention Versus Usual Care for Adults With Severe and Complex Obesity

RECRUITING
NCT06321458Phase NACarsten DirksenStarted 2024-04-29
Intensive weight loss interventionUsual care
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation
Obesity

Intensive Weight Loss Intervention Versus Usual Care for Adults With Obesity

ACTIVE NOT RECRUITING
NCT06321432Phase NACarsten DirksenStarted 2024-06-05
Intensive weight loss interventionUsual care
Obesity

Intensive Weight Loss Intervention Versus Bariatric Surgery for Adults With Severe and Complex Obesity: the LightBAR Randomised Trial

RECRUITING
NCT06309238Phase NACarsten DirksenStarted 2024-05-08
Intensive weight loss interventionBariatric surgery

External Resources

Links to major genomics databases and tools