SOX11

protein-coding

SRY-box transcription factor 11, the group of SRY-box transcription factors

Gene summary

This intronless gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. The protein may function in the developing nervous system and play a role in tumorigenesis. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003108.4

Inheritance

ClinVar variants

P:100U:221B:132

Top phenotype

Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism (Coffin-Siris syndrome 9)

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr2:5,692,384-5,701,385

External References & Databases

Ensembl (ENSG00000176887)

Transcript & Mutation Effects

hg38 • Region Span ~9.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Coffin-Siris syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015452

Submitter: Orphanet

intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014376

Submitter: PanelApp Australia

intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014376

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadismDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014376

Submitter: Ambry Genetics

intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadismDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014376

Submitter: G2P

SOX11-related complex neurodevelopmental disorder with or without congenital anomaliesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100626

Submitter: ClinGen

*SOX11* encodes a transcription factor that acts as a transcriptional activator. *SOX11* was first reported in relation to autosomal dominant SOX11-related complex neurodevelopmental disorder with or without congenital anomalies in 2014 (Tsurusaki et al., PMID: 24886874). The disorder is characterized by intellectual disability, microcephaly, short stature, low body weight, and dysmorphic features. Patients may also have ocular malformations, ocular apraxia, hypogonadotropic hypogonadism, structural brain malformations, renal malformations, or autism. Although initially reported as a form of Coffin-Siris syndrome, individuals with *SOX11* syndrome exhibit a distinctive pattern of blood DNA methylation that differentiates it from other BAFopathies (PMID: 35341651). Fourteen *de novo* variants (missense, nonsense, and frameshift) that have been reported in 14 probands in three publications (PMIDs: 24886874, 26543203, 35341651) are included in this curation. The majority of reported pathogenic and likely pathogenic variants are missense variants, located within or next to the high mobility group (HMG) box, a common motif in all SOX proteins that activate target genes via DNA binding. Therefore, the HMG box could be classified as a variant hotspot, further supported by several recurrent variants found in this domain. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by biochemical function. Variants in multiple genes of the SRY-related (SOX) transcription factor family are associated with developmental disorders termed SOXopathies; examples of SOX genes involved in syndromic neurodevelopmental disorders include *SOX2*, *SOX3*, *SOX4*, *SOX5*, *SOX6*, and *SOX10*. In summary, there is definitive evidence supporting the relationship between *SOX11* and autosomal dominant SOX11-related complex neurodevelopmental disorder with or without congenital anomalies. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 20, 2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism (Coffin-Siris syndrome 9)AD

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic; Endocrine

Rationale: Individuals have been described with hearling loss, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The condition can include hypogonadotropic hypogonadism, and surveillance in adolescence related to sexual maturation, including regarding potential pharmacologic interventions, is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease

Refs: 24886874; 33086258; 33785884; 35341651; 35642566

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SOX11 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 288

Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadismTotal: 128

Inborn genetic diseasesTotal: 87

SOX11-related disorderTotal: 42

not specifiedTotal: 36

Hypogonadotropic hypogonadismTotal: 16

Coffin-Siris syndrome 1Total: 2

Craniosynostosis syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003108.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			29 clinvar	78 clinvar	6 clinvar	113
missense	9 clinvar	60 clinvar	185 clinvar	38 clinvar	10 clinvar	302
nonsense	8 clinvar	7 clinvar	4 clinvar			19
start loss						0
frameshift	5 clinvar	11 clinvar	3 clinvar			19
splice donor/acceptor (+/-2bp)						0
Total	22	78	221	116	16	453

Highest pathogenic variant AF is 0.0000018587292

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003108.4	RefSeq	NP_003099.1	1	MANE Select
ENST00000322002.5	Ensembl	ENSP00000322568.3	1	MANE Select

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
sox11b	Danio rerio	Structure: caudal vein plexus Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

sox11b

Danio rerio

Structure: caudal vein plexus

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Preimplantation Embryo

Biological Process

negative regulation of transcription by RNA polymerase II
skeletal system development
kidney development
neural tube formation
lens morphogenesis in camera-type eye

Molecular Function

transcription regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
enhancer sequence-specific DNA binding
DNA-binding transcription activator activity, RNA polymerase II-specific

Cellular Component

nucleus
cytoplasm
nuclear transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000322002
Coding exons: 1
Length: 8718
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.26	146	246	0.594	0.0000114	2848
Missense (PolyPhen)		24	94.071	0.25513		1059
Synonymous	-2.95	153	113	1.35	0.00000577	867
Loss of Function	2.76	1	10.8	0.0927	4.63e-7	128

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional factor involved in the embryonic neurogenesis. May also have a role in tissue modeling during development. {ECO:0000269|PubMed:24886874}.;

Recessive Scores

pRec: 0.154

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.261

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium