SOX2

Chr 3AD

SRY-box transcription factor 2

Also known as: ANOP3, MCOPS3

NCBI Gene: 6657ENSG00000181449UniProt: P48431

This intronless gene encodes a member of the SRY-related HMG-box (SOX) family of transcription factors involved in the regulation of embryonic development and in the determination of cell fate. The product of this gene is required for stem-cell maintenance in the central nervous system, and also regulates gene expression in the stomach. Mutations in this gene have been associated with optic nerve hypoplasia and with syndromic microphthalmia, a severe form of structural eye malformation. This gene lies within an intron of another gene called SOX2 overlapping transcript (SOX2OT). [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Microphthalmia, syndromic 3MIM #206900
AD
Optic nerve hypoplasia and abnormalities of the central nervous systemMIM #206900
AD
317
ClinVar variants
144
Pathogenic / LP
0.71
pLI score
6
Active trials
Clinical Summary— SOX2
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.71) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
144 Pathogenic / Likely Pathogenic· 102 VUS of 317 total submissions
💊
Clinical Trials
6 active or recruiting trials — potential therapeutic options may be available

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.
0.57LOEUF
pLI 0.707
Z-score 2.36
OE 0.12 (0.04–0.57)
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.
2.12Z-score
OE missense 0.57 (0.48–0.66)
107 obs / 189.1 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.0.12 (0.04–0.57)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.57 (0.48–0.66)
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.1.15
0≤1.21.6
LoF obs/exp: 1 / 8.3Missense obs/exp: 107 / 189.1Syn Z: -1.06

ClinVar Variant Classifications

317 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic116
Likely Pathogenic28
VUS102
Likely Benign42
Benign19
Conflicting10
116
Pathogenic
28
Likely Pathogenic
102
VUS
42
Likely Benign
19
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
42
10
64
0
116
Likely Pathogenic
9
9
10
0
28
VUS
0
84
6
12
102
Likely Benign
0
8
3
31
42
Benign
0
5
8
6
19
Conflicting
—10
Total511169149317

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

View in ClinVar →

Protein Context — Lollipop Plot

SOX2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SOX2-related microphthalmia syndromic

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
SRY-BOX 2; SOX2
MIM #184429 · *

Microphthalmia, syndromic 3

MIM #206900

Molecular basis of disorder known

Autosomal dominant

Optic nerve hypoplasia and abnormalities of the central nervous system

MIM #206900

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SOX2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance.
Ku SY et al.·Science
2017
Suspension culture improves iPSC expansion and pluripotency phenotype.
Cuesta-Gomez N et al.·Stem Cell Res Ther
2023
SOX2 promotes chemoresistance, cancer stem cells properties, and epithelial-mesenchymal transition by β-catenin and Beclin1/autophagy signaling in colorectal cancer.
Zhu Y et al.·Cell Death Dis
2021
SOX2 drives esophageal squamous carcinoma by reprogramming lipid metabolism and histone acetylation landscape.
Wang Z et al.·Nat Commun
2025
Super-Enhancer Driven LIF/LIFR-STAT3-SOX2 Regulatory Feedback Loop Promotes Cancer Stemness in Head and Neck Squamous Cell Carcinoma.
Li J et al.·Adv Sci (Weinh)
2024
Precise targeting of transcriptional co-activators YAP/TAZ annihilates chemoresistant brCSCs by alteration of their mitochondrial homeostasis.
Talukdar PD et al.·Signal Transduct Target Ther
2025
Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1.
Chen HY et al.·Nat Commun
2022
The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer.
Singh N et al.·Nat Commun
2021
Targeting SOX2 in anticancer therapy.
Hüser L et al.·Expert Opin Ther Targets
2018Review
A pan-cancer analysis shows immunoevasive characteristics in NRF2 hyperactive squamous malignancies.
Härkönen J et al.·Redox Biol
2023
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
Open Angle Glaucoma (OAG)NAION( Non-arteritic Anterior Ischemic Optic Neuropathy)

Evaluating ER-100 for Safety in People With Glaucoma or Non-Arteritic Anterior Ischemic Optic Neuropathy (Optic Nerve Conditions)

RECRUITING
NCT07290244Phase PHASE1Life Biosciences Inc.Started 2026-03-02
ER-100 epigenetic therapy
Infertility, MaleGene AbnormalitySterility, Male

Spermatogonial Differentiation Via Testicular Organoid

RECRUITING
NCT06841861Phase PHASE1, PHASE2CellARTs Inc.Started 2024-03-28
Stem cellGenetic ScreeningGenetic Reprogramming
Lung Non-Small Cell CarcinomaStage IV Lung Cancer AJCC v8

A Multiple Antigen Vaccine (STEMVAC) for the Treatment of Patients With Stage IV Non-Small Cell Lung Cancer

ACTIVE NOT RECRUITING
NCT05242965Phase PHASE2University of WashingtonStarted 2023-03-24
CD105/Yb-1/SOX2/CDH3/MDM2-polyepitope Plasmid DNA VaccineSargramostimComputed Tomography
Anatomic Stage IV Breast Cancer AJCC v8Metastatic HER2-Negative Breast CarcinomaMetastatic Hormone Receptor-Positive Breast Carcinoma

A Vaccine (STEMVAC) With Standard Endocrine-Based Therapy or Chemotherapy for the Treatment of Metastatic Hormone Receptor Positive, HER2 Negative Breast Cancer

RECRUITING
NCT07112053Phase PHASE2University of WashingtonStarted 2025-11-17
CD105/Yb-1/SOX2/CDH3/MDM2-polyepitope Plasmid DNA VaccineCapecitabineComputed Tomography
Prostate Cancer

GU-01: Glycyrrhizin in Prostate Cancer

RECRUITING
NCT06378346Phase PHASE2University of Illinois at ChicagoStarted 2024-07-25
ObservationGlycyrrhizin - 75 mgGlycyrrhizin - 150 mg
Fistula Repair

Endoscopic Injection of Autologous, Activated and Emulsified Fat in Chronic Fistulas of the Gastrointestinal Tract and Pelvic Organs

RECRUITING
NCT06930079Fondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-03-20

External Resources

Links to major genomics databases and tools