SASH1

Summary

SASH1 (SAM and SH3 domain containing 1, HGNC:19182) is a protein-coding gene on chromosome 6q24.3-q25.1, encoding SAM and SH3 domain-containing protein 1 (O94885). Is a positive regulator of NF-kappa-B signaling downstream of TLR4 activation.

This gene encodes a scaffold protein involved in the TLR4 signaling pathway that may stimulate cytokine production and endothelial cell migration in response to invading pathogens. The encoded protein has also been described as a potential tumor suppressor that may negatively regulate proliferation, apoptosis, and invasion of cancer cells, and reduced expression of this gene has been observed in multiple human cancers. Mutations in this gene may be associated with abnormal skin pigmentation in human patients.

Source: NCBI Gene 23328 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dyschromatosis universalis hereditaria 1 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 358 total — 1 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 17
• MANE Select transcript: NM_015278

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19182
Approved symbol	SASH1
Name	SAM and SH3 domain containing 1
Location	6q24.3-q25.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0790, dJ323M4.1, SH3D6A
Ensembl gene	ENSG00000111961
Ensembl biotype	protein_coding
OMIM	607955
Entrez	23328

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 10 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000367467, ENST00000367469, ENST00000470750, ENST00000635873, ENST00000635969, ENST00000636279, ENST00000637029, ENST00000637469, ENST00000637498, ENST00000637729, ENST00000860456, ENST00000860457, ENST00000933694, ENST00000946240, ENST00000946241, ENST00000946242, ENST00000946243

RefSeq mRNA: 3 — MANE Select: NM_015278 NM_001346505, NM_001346506, NM_015278

CCDS: CCDS5212

Canonical transcript exons

ENST00000367467 — 20 exons

Exon	Start	End
ENSE00000765041	148546015	148546146
ENSE00000765045	148534751	148534901
ENSE00000765048	148531526	148531661
ENSE00000765051	148525291	148525365
ENSE00000765052	148519547	148519893
ENSE00000765053	148514324	148514456
ENSE00000765054	148487614	148487715
ENSE00000799100	148540443	148540556
ENSE00000799101	148543680	148544818
ENSE00001444573	148548295	148552044
ENSE00001444575	148342838	148343223
ENSE00001612635	148390134	148390262
ENSE00001646510	148440184	148440234
ENSE00002437067	148532797	148532966
ENSE00002465315	148471417	148471503
ENSE00002488756	148527453	148527596
ENSE00002490933	148474110	148474222
ENSE00002493377	148468545	148468585
ENSE00002527854	148533771	148533980
ENSE00003567662	148440358	148440407

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.3463 / max 487.5155, expressed in 1620 samples.

FANTOM5 promoters (23 alternative TSS)

Promoter ID	TPM avg	Samples expressed
70421	5.3557	1319
70414	3.7258	518
70420	3.1756	1306
70423	1.9112	844
70440	1.6065	591
70441	1.0554	480
70419	0.5391	286
70435	0.4200	210
70422	0.4058	191
70413	0.3079	194

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
synovial joint	UBERON:0002217	98.60	gold quality
lateral globus pallidus	UBERON:0002476	98.35	gold quality
skin of hip	UBERON:0001554	98.13	gold quality
subthalamic nucleus	UBERON:0001906	98.12	gold quality
upper leg skin	UBERON:0004262	98.04	gold quality
esophagus squamous epithelium	UBERON:0006920	98.01	gold quality
inferior vagus X ganglion	UBERON:0005363	97.63	gold quality
epithelium of esophagus	UBERON:0001976	97.53	gold quality
oral cavity	UBERON:0000167	97.51	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.51	gold quality
calcaneal tendon	UBERON:0003701	97.21	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.19	gold quality
superior vestibular nucleus	UBERON:0007227	97.03	gold quality
medulla oblongata	UBERON:0001896	97.02	gold quality
pharyngeal mucosa	UBERON:0000355	97.00	gold quality
substantia nigra pars compacta	UBERON:0001965	97.00	gold quality
corpus callosum	UBERON:0002336	96.83	gold quality
ventral tegmental area	UBERON:0002691	96.78	gold quality
squamous epithelium	UBERON:0006914	96.62	gold quality
tibia	UBERON:0000979	96.56	gold quality
endothelial cell	CL:0000115	96.49	gold quality
parietal pleura	UBERON:0002400	96.33	gold quality
dorsal plus ventral thalamus	UBERON:0001897	96.32	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.28	gold quality
globus pallidus	UBERON:0001875	96.23	gold quality
penis	UBERON:0000989	96.18	gold quality
gingiva	UBERON:0001828	96.17	gold quality
mammary duct	UBERON:0001765	96.12	gold quality
urethra	UBERON:0000057	96.10	gold quality
adipose tissue	UBERON:0001013	96.08	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	61.87
E-CURD-119	yes	32.87
E-HCAD-25	yes	19.73
E-MTAB-6678	yes	6.40
E-MTAB-9067	yes	6.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

204 targeting SASH1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505

Literature-anchored findings (GeneRIF, showing 40)

• tumor suppressor gene possibly involved in tumorigenesis of breast and other solid cancers (PMID:12771949)
• Downregulated expression of the candidate tumour suppressor gene SASH1 is associated with colon cancer (PMID:17088907)
• A mechanistic role for SASH1 in tumor formation by regulating the adhesive and migratory behavior of cancer cells has been shown. (PMID:21820526)
• The SASH1 gene may inhibit A549 cell growth and proliferation as well as promote cellular apoptosis. The overexpression of the SASH1 gene may also be related to the decreased migration of A549 human lung cancer cells. (PMID:22488244)
• Loss of SASH1 is associated with glioma. (PMID:22915266)
• The SASH1 gene is blocked cyclin B1-Cdc2 binding, either directly or indirectly, leading to G2/M arrest. (PMID:23023727)
• Overexpression of SASH1 might be associated with the inhibition of growth, proliferation, and invasion osteosarcoma cells. (PMID:23108792)
• SASH1 regulates IQGAP1-E-Cadherin signalling and crosstalking between GPCR signalling, calmodulin signalling for the modulation of melanocytes invasion. (PMID:23333244)
• Propose that increase of DNA methylation level in the promoter region of gene SASH1, particularly CpG_26.27 or CpG_54.55 sites, possibly repressed SASH1 expression in breast cancer. (PMID:24344014)
• Data suggest that SASH1 (SAM and SH3 domain-containing protein 1) should be added to the list of genes responsible for autosomal-dominant and -recessive genodermatosis. (PMID:25315659)
• SASH1 Is Involved in an Autosomal Dominant Lentiginous Phenotype. (PMID:26203640)
• SASH1 expression is increased in atherosclerotic carotids in smokers and its silencing affects endothelial angiogenic functions (PMID:26318107)
• Two SNPs were significantly associated with rotator cuff tearing, residing in SAP30BP on chromosome 17 and SASH1 on chromosome 6. (PMID:26350878)
• SASH1 expression strongly correlated with glioma grades, showing higher expression at a lower grade. (PMID:26424902)
• The loss or inhibition of SASH1 expression may play an important role in thyroid cancer development, invasion, and metastasis. (PMID:26722413)
• Overexpression of SASH1 inhibits TGF-beta1-induced EMT. (PMID:27178818)
• Overexpression of SASH1 suppressed the expression of Shh. (PMID:27178819)
• SASH1 is prognostic in breast cancer and could have subtype-dependent effects on breast cancer progression. (PMID:27637080)
• SASH1 is cleaved by caspase-3 following Ultraviolet C-induced apoptosis. (PMID:27831555)
• Case Report: SASH1 missense mutation in a Chinese Family with multiple lentigines. (PMID:27840890)
• a novel p53/POMC/Galphas/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype. (PMID:27885802)
• Data show that SAM and SH3 domain containing 1 protein (SASH1) binds with mitogen-activated protein kinase kinase 2 (MAP2K2), and SASH1 mutations promote binding between SASH1 and MAP2K2. (PMID:28382689)
• SASH1 may inhibit hepatocarcinoma cell invasion and metastasis through down-regulating the Shh-Gli1 and PI3K-AKT pathways (PMID:28600143)
• SASH1 acts through NOTCH1 and its inhibitor DLK1 in a three-dimensional model of lumenogenesis involving CEACAM1. (PMID:28823832)
• findings suggested that SASH1 can be useful as a new prognostic marker and therapeutic target in cervical cancer patients. (PMID:28975991)
• Our clinical findings suggest that downregulated SASH1 expression could be used as an independent biomarker for poor prognosis in gastric carcinoma. (PMID:29320755)
• These data further confirm that the SLY domain is critical for mediation of melanogenesis and suggest that Y551 may be a mutation hotspot for dyschromatosis universalis hereditaria. The p.M595T is the first heterozygous missense mutation reported in the SH3 domain. (PMID:29956681)
• that SASH1 was a target gene of miR-17 (PMID:30396754)
• Findings indicate that miR-130b was highly expressed, while SAM and SH3 domain containing 1 protein (SASH1) was the opposite in both the oesophageal squamous cell carcinoma (ESCC) tissues and cells. (PMID:30443973)
• SASH1 is an inhibitor of CRKL-mediated SRC signaling. (PMID:30480076)
• SASH1 suppresses triple-negative breast cancer cell invasion through YAP-ARHGAP42-actin axis. (PMID:32523092)
• Involvement of SASH1 in the Maintenance of Stable Cell-Cell Adhesion. (PMID:32586229)
• Paired like homeodomain 1 and SAM and SH3 domain-containing 1 in the progression and prognosis of head and neck squamous cell carcinoma. (PMID:32905855)
• Five novel mutations in SASH1 contribute to lentiginous phenotypes in Japanese families. (PMID:32981204)
• SASH1 is a prognostic indicator and potential therapeutic target in non-small cell lung cancer. (PMID:33122723)
• Expression of SASH1 in Preeclampsia and Its Effects on Human Trophoblast. (PMID:33134379)
• Two novel SASH1 mutations in Chinese families with dyschromatosis universalis hereditaria. (PMID:34028087)
• Genetic and phenotypic heterogeneity of multiple lentigines and precise diagnosis in four Chinese families with multiple lentigines. (PMID:37056170)
• Two novel mutations in SASH1 identified in a familial and a sporadic generalized lentiginosis phenotype in Koreans. (PMID:37337450)
• Human Endogenous Retrovirus-H-Derived miR-4454 Inhibits the Expression of DNAJB4 and SASH1 in Non-Muscle-Invasive Bladder Cancer. (PMID:37510314)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sash1a	ENSDARG00000007179
danio_rerio	sash1b	ENSDARG00000058853
mus_musculus	Sash1	ENSMUSG00000015305
rattus_norvegicus	Sash1	ENSRNOG00000013160

Paralogs (2): SASH3 (ENSG00000122122), SAMSN1 (ENSG00000155307)

Protein

Protein identifiers

SAM and SH3 domain-containing protein 1 — O94885 (reviewed: O94885)

Alternative names: Proline-glutamate repeat-containing protein

All UniProt accessions (4): O94885, A0A1B0GVF9, A0A1B0GVI0, A0A1B0GWB9

UniProt curated annotations — full annotation on UniProt →

Function. Is a positive regulator of NF-kappa-B signaling downstream of TLR4 activation. It acts as a scaffold molecule to assemble a molecular complex that includes TRAF6, MAP3K7, CHUK and IKBKB, thereby facilitating NF-kappa-B signaling activation. Regulates TRAF6 and MAP3K7 ubiquitination. Involved in the regulation of cell mobility. Regulates lipolysaccharide (LPS)-induced endothelial cell migration. Is involved in the regulation of skin pigmentation through the control of melanocyte migration in the epidermis.

Subunit / interactions. Interacts with GNAS. Interacts with IQGAP1. Interacts with TRAF6 (via C-terminus); the interaction is LPS-dependent. Interacts with MAP3K7, CHUK and IKBKB.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed ubiquitously, with highest levels in lung, placenta, spleen and thymus. Down-regulated in the majority (74%) of breast tumors in comparison with corresponding normal breast epithelial tissues. Expressed in the epidermis, epidermal keratinocytes, dermal fibroblasts and melanocytes.

Disease relevance. Dyschromatosis universalis hereditaria 1 (DUH1) [MIM:127500] A form of dyschromatosis universalis, an autosomal dominant pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules distributed randomly over the body, that appear in infancy or early childhood. The trunk and extremities are the dominant sites of abnormal pigmentation. Facial lesions can be seen in 50% of affected individuals, but involvement of palms and soles is unusual. Abnormalities of hair and nails have also been reported. Dyschromatosis universalis hereditaria may be associated with abnormalities of dermal connective tissue, nerve tissue, or other systemic complications. The disease is caused by variants affecting the gene represented in this entry. Cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratoderma (CAPOK) [MIM:618373] An autosomal recessive genodermatosis characterized by hypo- and hyperpigmented macular skin lesions, progressive alopecia, palmoplantar keratoderma, dystrophic nails, teeth abnormalities and a predisposition to squamous cell carcinoma. The disease may be caused by variants affecting the gene represented in this entry.

RefSeq proteins (3): NP_001333434, NP_001333435, NP_056093* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR001660	SAM	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR021090	SPIDER	Domain
IPR035720	SASH1_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR037627	SASH1_SAM_repeat1	Domain
IPR037630	SASH1_SAM_repeat2	Domain
IPR051725	SAM-SH3_domain_protein	Family
IPR058666	SASH1/NUB1_homeodomain	Domain

Pfam: PF00536, PF07647, PF07653, PF12485, PF26285

UniProt features (56 total): region of interest 11, sequence variant 11, compositionally biased region 8, modified residue 7, strand 6, helix 6, domain 3, sequence conflict 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2DL0	SOLUTION NMR
2EBP	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94885-F1	54.90	0.18

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (7): 90, 248, 407, 614, 821, 839, 858

Mutagenesis-validated functional residues (1):

Position	Phenotype
852–860	abolishes interaction with traf6.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 399 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GGGACCA_MIR133A_MIR133B, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_CELLULAR_RESPONSE_TO_LIPID, TGCACTT_MIR519C_MIR519B_MIR519A, PEREZ_TP63_TARGETS, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_EPITHELIAL_CELL_MIGRATION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (10): protein polyubiquitination (GO:0000209), positive regulation of endothelial cell migration (GO:0010595), regulation of epithelial cell migration (GO:0010632), positive regulation of lipopolysaccharide-mediated signaling pathway (GO:0031666), positive regulation of JUN kinase activity (GO:0043507), positive regulation of angiogenesis (GO:0045766), regulation of protein K63-linked ubiquitination (GO:1900044), positive regulation of p38MAPK cascade (GO:1900745), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), regulation of protein autoubiquitination (GO:1902498)

GO Molecular Function (5): G-protein alpha-subunit binding (GO:0001965), protein kinase binding (GO:0019901), mitogen-activated protein kinase kinase kinase binding (GO:0031435), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
binding	2
protein ubiquitination	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
epithelial cell migration	1
regulation of cell migration	1
regulation of multicellular organismal process	1
positive regulation of response to biotic stimulus	1
positive regulation of signal transduction	1
lipopolysaccharide-mediated signaling pathway	1
regulation of lipopolysaccharide-mediated signaling pathway	1
positive regulation of response to external stimulus	1
JUN kinase activity	1
positive regulation of MAP kinase activity	1
regulation of JUN kinase activity	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
protein K63-linked ubiquitination	1
regulation of protein polyubiquitination	1
p38MAPK cascade	1
positive regulation of MAPK cascade	1
regulation of p38MAPK cascade	1
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
regulation of protein ubiquitination	1
protein autoubiquitination	1
protein binding	1
kinase binding	1
protein kinase binding	1
molecular_function	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
cellular_component	1

Protein interactions and networks

STRING

758 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SASH1	ADAR	P55265	688
SASH1	ITPK1	Q13572	552
SASH1	SRC	P12931	509
SASH1	SAP30BP	Q9UHR5	506
SASH1	SAMD5	Q5TGI4	478
SASH1	PALLD	Q8WX93	473
SASH1	LRRN3	Q9H3W5	435
SASH1	MBIP	Q9NS73	434
SASH1	MTRF1L	Q9UGC7	422
SASH1	HACD3	Q9P035	413
SASH1	AADAT	Q8N5Z0	404
SASH1	CDKN1C	P49918	399
SASH1	CAPNS2	Q96L46	397
SASH1	SLC17A4	Q9Y2C5	394
SASH1	CCDC159	P0C7I6	391

IntAct

42 interactions, top by confidence:

A	B	Type	Score
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
SASH1	SFN	psi-mi:“MI:0915”(physical association)	0.540
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
NCK1	SASH1	psi-mi:“MI:0915”(physical association)	0.400
MED28	SASH1	psi-mi:“MI:0915”(physical association)	0.400
SASH1	E6	psi-mi:“MI:0915”(physical association)	0.370
SASH1	E7	psi-mi:“MI:0915”(physical association)	0.370
SASH1	SKIL	psi-mi:“MI:0915”(physical association)	0.370
HTT	SASH1	psi-mi:“MI:0915”(physical association)	0.370
SASH1	HTT	psi-mi:“MI:0915”(physical association)	0.370
NS1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAB	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAQ	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
BMH1	SASH1	psi-mi:“MI:0914”(association)	0.350
SASH1	Ywhab	psi-mi:“MI:0914”(association)	0.350

BioGRID (79): SASH1 (Affinity Capture-MS), SASH1 (Affinity Capture-MS), SASH1 (Affinity Capture-RNA), AFF1 (Two-hybrid), AKAP10 (Two-hybrid), ARRB1 (Two-hybrid), ASCC2 (Two-hybrid), C1D (Two-hybrid), CCNDBP1 (Two-hybrid), CNKSR1 (Two-hybrid), CRK (Two-hybrid), CRKL (Two-hybrid), CTNNA1 (Two-hybrid), EPS8L2 (Two-hybrid), IKBKB (Two-hybrid)

ESM2 similar proteins: A0FKI7, A1L1M4, A5X7A0, A7XYJ6, A8MW92, E1BE02, F8VPQ2, O18805, O35613, O94885, P59598, P59808, Q0VGB7, Q13029, Q28IG6, Q4V9H5, Q5M7D6, Q5R9U6, Q5RJ80, Q5TJE1, Q5XG73, Q5ZHQ6, Q5ZM88, Q5ZMU6, Q63755, Q640U0, Q641E3, Q6DCQ0, Q6I6G8, Q6KAQ7, Q6P964, Q6ZQ03, Q76L83, Q76LL6, Q76N89, Q7TT18, Q8BLG0, Q8BZ32, Q8C9B9, Q8CCJ9

Diamond homologs: A0JN71, O75995, O94885, P57725, P59672, P59808, Q8K352, Q92625, Q9NSI8, Q9XYM0, Q5TGI4, A0A8I3NFE2, A5PMU4, A8JQ65, B3LXF2, B3NYS4, B4I4Y1, B4JHJ7, B4K6T8, B4PRE2, B4R0A5, D7PF45, O15357, O73878, P09759, P0C6S7, P28693, P29323, P54753, P54754, P54755, P54756, P54760, P54761, P54762, P54763, Q07494, Q07498, Q09YL6, Q2I6J1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	7	333.1×	1e-15
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	293.9×	2e-15
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	293.9×	2e-15
Activation of BH3-only proteins	7	217.2×	2e-14
RHO GTPases activate PKNs	7	138.8×	5e-13
Intrinsic Pathway for Apoptosis	7	128.1×	8e-13
FOXO-mediated transcription	5	105.0×	5e-09
SARS-CoV-1-host interactions	7	76.9×	3e-11

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	107.8×	7e-08
intracellular protein localization	7	43.1×	2e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

358 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	12
Uncertain significance	222
Likely benign	40
Benign	50

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
624631	NM_015278.5(SASH1):c.1527_1530dup (p.Leu511fs)	Pathogenic
2430242	NM_015278.5(SASH1):c.1548T>A (p.Ser516Arg)	Likely pathogenic
2430283	NM_015278.5(SASH1):c.1811C>A (p.Thr604Lys)	Likely pathogenic
2444026	NM_015278.5(SASH1):c.1574C>T (p.Thr525Ile)	Likely pathogenic
3775235	NM_015278.5(SASH1):c.1546A>C (p.Ser516Arg)	Likely pathogenic
3776092	NM_015278.5(SASH1):c.1930C>T (p.Arg644Trp)	Likely pathogenic
4682034	NM_015278.5(SASH1):c.1592C>G (p.Ser531Cys)	Likely pathogenic
624625	NM_015278.5(SASH1):c.1651T>G (p.Tyr551Asp)	Likely pathogenic
624626	NM_015278.5(SASH1):c.1544T>C (p.Leu515Pro)	Likely pathogenic
624627	NM_015278.5(SASH1):c.1525G>A (p.Glu509Lys)	Likely pathogenic
624629	NM_015278.5(SASH1):c.1556G>A (p.Ser519Asn)	Likely pathogenic
624632	NM_015278.5(SASH1):c.1519T>G (p.Ser507Ala)	Likely pathogenic
624633	NM_015278.5(SASH1):c.1651T>C (p.Tyr551His)	Likely pathogenic

SpliceAI

3908 predictions. Top by Δscore:

Variant	Effect	Δscore
6:148343224:G:GG	donor_gain	1.0000
6:148390119:T:TA	acceptor_gain	1.0000
6:148390124:A:AG	acceptor_gain	1.0000
6:148390125:C:G	acceptor_gain	1.0000
6:148390131:CAG:C	acceptor_loss	1.0000
6:148390132:A:AG	acceptor_gain	1.0000
6:148390132:AG:A	acceptor_gain	1.0000
6:148390132:AGGAC:A	acceptor_gain	1.0000
6:148390133:G:GT	acceptor_gain	1.0000
6:148390133:GG:G	acceptor_gain	1.0000
6:148390133:GGA:G	acceptor_gain	1.0000
6:148390133:GGAC:G	acceptor_gain	1.0000
6:148390133:GGACG:G	acceptor_gain	1.0000
6:148390257:G:GT	donor_gain	1.0000
6:148390258:AAGTG:A	donor_gain	1.0000
6:148390260:GTG:G	donor_gain	1.0000
6:148390261:TG:T	donor_gain	1.0000
6:148390262:GG:G	donor_gain	1.0000
6:148390263:G:GG	donor_gain	1.0000
6:148390264:T:A	donor_loss	1.0000
6:148440357:GGA:G	acceptor_gain	1.0000
6:148440404:GAAA:G	donor_gain	1.0000
6:148440408:G:GG	donor_gain	1.0000
6:148468543:A:AG	acceptor_gain	1.0000
6:148468544:G:GG	acceptor_gain	1.0000
6:148471415:A:G	acceptor_gain	1.0000
6:148471528:G:GG	donor_gain	1.0000
6:148474101:A:AG	acceptor_gain	1.0000
6:148474102:A:G	acceptor_gain	1.0000
6:148474108:A:AG	acceptor_gain	1.0000

AlphaMissense

8133 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:148474131:C:A	A179D	1.000
6:148474146:T:C	M184T	1.000
6:148474161:G:C	R189P	1.000
6:148474164:T:A	I190N	1.000
6:148474164:T:C	I190T	1.000
6:148474164:T:G	I190S	1.000
6:148474170:T:A	L192Q	1.000
6:148474170:T:C	L192P	1.000
6:148474173:T:A	M193K	1.000
6:148474173:T:C	M193T	1.000
6:148474173:T:G	M193R	1.000
6:148474174:G:A	M193I	1.000
6:148474174:G:C	M193I	1.000
6:148474174:G:T	M193I	1.000
6:148474182:T:A	V196D	1.000
6:148474185:A:T	K197I	1.000
6:148474197:T:G	I201S	1.000
6:148474211:G:C	A206P	1.000
6:148474215:T:C	L207P	1.000
6:148474217:G:C	A208P	1.000
6:148487615:T:C	L210P	1.000
6:148514376:T:C	L261S	1.000
6:148514385:T:C	L264P	1.000
6:148525312:T:C	F411L	1.000
6:148525314:T:A	F411L	1.000
6:148525314:T:G	F411L	1.000
6:148531625:A:C	S510R	1.000
6:148531627:T:A	S510R	1.000
6:148531627:T:G	S510R	1.000
6:148531629:T:A	L511H	1.000

dbSNP variants (sampled 300 via entrez): RS1000000673 (6:148230198 A>G), RS1000030921 (6:148477224 C>A,T), RS1000032641 (6:148250658 G>A), RS1000037541 (6:148336816 A>G), RS1000039947 (6:148244134 C>A,G), RS1000052515 (6:148495192 T>G), RS1000071108 (6:148518123 C>A,G), RS1000075289 (6:148212027 G>T), RS1000096884 (6:148359854 A>C,G), RS1000097698 (6:148507511 C>G,T), RS1000100672 (6:148419205 A>G), RS1000100742 (6:148236735 C>T), RS1000106350 (6:148413010 G>A,C), RS1000111194 (6:148278296 C>A), RS1000116039 (6:148200762 G>A,C)

Disease associations

OMIM: gene MIM:607955 | disease phenotypes: MIM:127500, MIM:277900, MIM:614558

GenCC curated gene-disease

Disease	Classification	Inheritance
dyschromatosis universalis hereditaria 1	Strong	Autosomal dominant
pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome	Supportive	Autosomal recessive
familial generalized lentiginosis	Supportive	Autosomal dominant

Mondo (6): dyschromatosis universalis hereditaria 1 (MONDO:0024524), alopecia (MONDO:0004907), Wilson disease (MONDO:0010200), developmental and epileptic encephalopathy, 13 (MONDO:0013801), pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome (MONDO:0018657), familial generalized lentiginosis (MONDO:0007891)

Orphanet (3): Alopecia (Orphanet:79364), Wilson disease (Orphanet:905), Non-specific early-onset epileptic encephalopathy (Orphanet:442835)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000524	Conjunctival telangiectasia
HP:0000958	Dry skin
HP:0000982	Palmoplantar keratoderma
HP:0001034	Hypermelanotic macule
HP:0001480	Freckling
HP:0001596	Alopecia
HP:0002293	Alopecia of scalp
HP:0002860	Squamous cell carcinoma
HP:0003593	Infantile onset
HP:0005987	Multinodular goiter
HP:0006480	Premature loss of teeth
HP:0007441	Hyperpigmented/hypopigmented macules
HP:0008404	Nail dystrophy
HP:0009719	Hypomelanotic macule
HP:0040189	Scaling skin

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000189_40	Protein quantitative trait loci	1.000000e-06
GCST000484_3	Alzheimer’s disease	8.000000e-06
GCST000909_4	Type 2 diabetes nephropathy	7.000000e-07
GCST001856_14	Thyroid hormone levels	2.000000e-08
GCST001856_37	Thyroid hormone levels	3.000000e-08
GCST003115_2	Rotator cuff tears	2.000000e-07
GCST003542_110	Night sleep phenotypes	1.000000e-06
GCST003988_12	Hypothyroidism	1.000000e-14
GCST004110_17	Gait speed in old age	2.000000e-06
GCST005588_30	Idiopathic dilated cardiomyopathy	9.000000e-06
GCST006138_44	Resting-state electroencephalogram vigilance	5.000000e-06
GCST007576_196	Chronotype	7.000000e-09
GCST009084_1	Pneumococcal meningitis x streptococcus pneumoniae antigen allele interaction	4.000000e-09
GCST009391_519	Metabolite levels	4.000000e-06
GCST010653_28	Thyroid stimulating hormone levels	1.000000e-17
GCST011365_158	Myocardial infarction	1.000000e-05

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004467	insulin measurement
EFO:0004730	hormone measurement
EFO:0009094	idiopathic dilated cardiomyopathy
EFO:0004357	electroencephalogram measurement
EFO:0008328	chronotype measurement
EFO:0010271	bacterial pathogen genotype measurement
EFO:0010117	pyruvate measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000505	Alopecia	C17.800.329.937.122; C23.300.035
D006527	Hepatolenticular Degeneration	C06.552.413; C10.228.140.079.493; C10.228.140.163.100.360; C10.228.662.400; C10.574.500.487; C16.320.400.361; C16.320.565.189.360; C16.320.565.618.403; C18.452.132.100.360; C18.452.648.189.360; C18.452.648.618.403
C567273	Dyschromatosis Universalis Hereditaria 1 (supp.)
C573023	Lentiginosis Profusa (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects splicing, decreases expression, affects cotreatment, increases abundance, increases expression	6
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression, affects methylation	6
Valproic Acid	affects expression, decreases methylation, increases expression	6
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, increases expression	5
Tobacco Smoke Pollution	decreases expression, increases expression, increases methylation	3
bisphenol A	increases expression, affects methylation, affects cotreatment, decreases methylation	2
Air Pollutants	decreases expression, increases abundance	2
Arsenic	affects cotreatment, increases abundance, increases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	decreases expression	1
tungsten carbide	affects cotreatment, decreases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
9,10-dihydro-9,10-dihydroxybenzo(a)pyrene	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
glycidamide	decreases expression	1
CGP 52608	affects binding, increases reaction	1
trans-10,cis-12-conjugated linoleic acid	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00176943	PHASE4	COMPLETED	Characteristics of T Cells From Alopecia Areata Scalp Skin Before and After Treatment With Aldara 5%
NCT00176969	PHASE4	COMPLETED	Response of Topical Capsaicin in Alopecia Areata
NCT00176982	PHASE4	COMPLETED	Plaquenil for Alopecia Areata, Alopecia Totalis
NCT00177021	PHASE4	COMPLETED	Aldara for the Treatment of Extensive Alopecia Areata
NCT01023841	PHASE4	COMPLETED	Safety and Efficacy of Bimatoprost Solution in Treating Eyelash Loss or Hypotrichosis in Children
NCT01111981	PHASE4	UNKNOWN	Safety and Efficacy of Clobetasol Propionate 0.05% E Foam in Alopecia
NCT01898806	PHASE4	TERMINATED	Intralesional Steroids in the Treatment of Alopecia Areata
NCT02350023	PHASE4	COMPLETED	Comparison of Topical Latanoprost vs Topical Corticosteroid in Treatment of Localized Alopecia Areata
NCT03473600	PHASE4	UNKNOWN	Cryotherapy Versus Steroids In Alopecia Areata:Trichoscopic Evaluation
NCT03535233	PHASE4	COMPLETED	Topical 5% Minoxidil and Potent Topical Corticosteroid Versus Intralesional Corticosteroid in the Treatment of Alopecia Areata
NCT03630198	PHASE4	COMPLETED	Pain Outcomes Following Intralesional Corticosteroid Injections
NCT03800979	PHASE4	COMPLETED	Effectiveness and Safety of Tofacitinib in Patients With Extensive and Recalcitrant Alopecia Areata
NCT04003376	PHASE4	UNKNOWN	Efficacy of Fractional CO2 Laser as a Mono- or Adjuvant Therapy for Alopecia Areata
NCT04228029	PHASE4	UNKNOWN	Comparative Study for Treatment of Alopecia Areata Using Carboxytherapy and Intralesional Steroids
NCT04412148	PHASE4	UNKNOWN	Modified SALT Score for Alopecia Areata
NCT04793945	PHASE4	UNKNOWN	Excimer Light and Topical Steroid in Treatment of Alopecia Areata
NCT05278858	PHASE4	TERMINATED	Needle-free Delivery of Intralesional Triamcinolone for Pediatric Alopecia Areata
NCT05926882	PHASE4	COMPLETED	Efficacy of Oral Apremilast in the Treatment of Alopecia Areata at the Tertiary Care Hospital, Karachi.
NCT06355856	PHASE4	UNKNOWN	Efficacy/ Safety of DNN.22.17.036 in Male Patients With Pattern Hair Loss
NCT06399783	PHASE4	NOT_YET_RECRUITING	Topical Simvastatin Versus Topical Steroid in Treatment of Alopecia Areata
NCT07174011	PHASE4	COMPLETED	Evaluation of the Efficacy and Safety of Oral Roflumilast Versus Intralesional Corticosteroids Injection (ILCs) in the Treatment of Alopecia Areata
NCT07381556	PHASE4	RECRUITING	Cyclosporine Or Methotrexate for Pediatric Alopecia Areata: Routine Clinical Care Effectiveness Study
NCT07406204	PHASE4	NOT_YET_RECRUITING	Tofacitinib vs Methotrexate for Severe Alopecia Areata (TOFA-MTX-AA)
NCT07453238	PHASE4	NOT_YET_RECRUITING	Comparison of Topical Calcipotriol and Intralesional Steroids in Alopecia Areata
NCT07459933	PHASE4	NOT_YET_RECRUITING	Topical Methotrexate vs Minoxidil for Localized Alopecia Areata
NCT00441116	PHASE3	COMPLETED	A Study To Assess The Efficacy And Safety Of Dutasteride 0.5mg Once Daily For 6 Months In The Treatment Of Male Subjects With Androgenetic Alopecia
NCT01145625	PHASE3	COMPLETED	Clinical Trial in Females With Female Pattern Hair Loss
NCT01453686	PHASE3	COMPLETED	A Trial of Clobetasol Propionate Versus Hydrocortisone in Children With Alopecia Areata
NCT01590238	PHASE3	COMPLETED	Enhancing Hair Density With Platelet Rich Fibrin Matrix (PRFM)
NCT01831791	PHASE3	COMPLETED	A Long-term Study to Determine Safety and Efficacy of Dutasteride in Male Subjects With Androgenetic Alopecia
NCT02014584	PHASE3	COMPLETED	Sexual Function in Men Receiving Dutasteride for Androgenetic Alopecia
NCT02037191	PHASE3	COMPLETED	The Efficiency Of The Methotrexate At Patients Affected By Grave Pelade
NCT02557074	PHASE3	COMPLETED	TREg Activation in the Treatment of the PELADE (Alopecia Areata)
NCT02691117	PHASE3	TERMINATED	Topical Garlic Concentrate for Alopecia Areata in Children
NCT03651752	PHASE3	TERMINATED	DPCP for the Treatment of Alopecia Areata
NCT03899259	PHASE3	COMPLETED	A Study of Baricitinib (LY3009104) in Adults With Severe or Very Severe Alopecia Areata
NCT04006457	PHASE3	COMPLETED	Long-Term PF-06651600 for the Treatment of Alopecia Areata
NCT04249128	PHASE3	COMPLETED	Nourishing Hair, Skin & Nails Supplement Study (Derm Aid)
NCT04518995	PHASE3	COMPLETED	Study to Evaluate the Efficacy and Safety of CTP-543 in Adults With Moderate to Severe Alopecia Areata (THRIVE-AA1)
NCT04721548	PHASE3	COMPLETED	Treatment of Androgenetic Alopecia in Men for 24 Weeks