SREBF2

Chr 22

sterol regulatory element binding transcription factor 2

Also known as: SREBP-2, SREBP2, bHLHd2

NCBI Gene: 6721ENSG00000198911UniProt: Q12772

This gene encodes a member of the a ubiquitously expressed transcription factor that controls cholesterol homeostasis by regulating transcription of sterol-regulated genes. The encoded protein contains a basic helix-loop-helix-leucine zipper (bHLH-Zip) domain and binds the sterol regulatory element 1 motif. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

285
ClinVar variants
20
Pathogenic / LP
0.21
pLI score
0
Active trials
Clinical Summary— SREBF2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
📋
ClinVar Variants
20 Pathogenic / Likely Pathogenic· 183 VUS of 285 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.38LOEUF
pLI 0.207
Z-score 5.05
OE 0.24 (0.15–0.38)
Moderately constrained

More LoF-intolerant than ~75% 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.
0.68Z-score
OE missense 0.93 (0.86–0.99)
605 obs / 653.9 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.0.24 (0.15–0.38)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.86–0.99)
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.1.01
0≤1.21.6
LoF obs/exp: 12 / 50.9Missense obs/exp: 605 / 653.9Syn Z: -0.18

ClinVar Variant Classifications

285 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic1
VUS183
Likely Benign19
Benign36
19
Pathogenic
1
Likely Pathogenic
183
VUS
19
Likely Benign
36
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
19
0
19
Likely Pathogenic
0
0
1
0
1
VUS
1
171
11
0
183
Likely Benign
0
7
3
9
19
Benign
0
4
25
7
36
Total11825916258

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

View in ClinVar →

Protein Context — Lollipop Plot

SREBF2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SREBF2-related complex dermatological, neurological, and skeletal abnormalities

moderate
ADDominant NegativeAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variant

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
Estrogen Induces LCAT to Maintain Cholesterol Homeostasis and Suppress Hepatocellular Carcinoma Development.
He W et al.·Cancer Res
2024
Lipophagy-mediated cholesterol synthesis inhibition is required for the survival of hepatocellular carcinoma under glutamine deprivation.
Kong Y et al.·Redox Biol
2023
Combination of bulk RNA and single-cell sequencing unveils PANoptosis-related immunological ecology hallmarks and classification for clinical decision-making in hepatocellular carcinoma.
Liu L et al.·Sci Rep
2024
Hypolipidemic effect and mechanism of Hedan tablet based on network pharmacology.
Huiming HU et al.·J Tradit Chin Med
2025Functional
Statin-associated regulation of hepatic PNPLA3 in patients without known liver disease.
Ahmed O et al.·J Intern Med
2025Cohort
Rhythm gene PER1 mediates ferroptosis and lipid metabolism through SREBF2/ALOX15 axis in polycystic ovary syndrome.
Chen Y et al.·Biochim Biophys Acta Mol Basis Dis
2024
Malignant Hepatoblast-Like Cells Sustain Stemness via IGF2-Dependent Cholesterol Accumulation in Hepatoblastoma.
Ding M et al.·Adv Sci (Weinh)
2025
Dominant missense variants in SREBF2 are associated with complex dermatological, neurological, and skeletal abnormalities.
Moulton MJ et al.·Genet Med
2024
Intracellullar cholesterol accumulation caused by HBV induces ATF6-mediated endoplasmic reticulum stress to trigger endoplasmic reticulophagy.
Lin Y et al.·Tissue Cell
2026
Expression of SREBF2 and HMGCR discriminates the viability of steatotic grafts for human liver transplantation.
Baulies A et al.·J Lipid Res
2025
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