SH2D4A

Summary

SH2D4A (SH2 domain containing 4A, HGNC:26102) is a protein-coding gene on chromosome 8p21.3, encoding SH2 domain-containing protein 4A (Q9H788). Inhibits estrogen-induced cell proliferation by competing with PLCG for binding to ESR1, blocking the effect of estrogen on PLCG and repressing estrogen-induced proliferation.

Enables phosphatase binding activity. Located in cytosol.

Source: NCBI Gene 63898 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 110 total
• MANE Select transcript: NM_022071

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26102
Approved symbol	SH2D4A
Name	SH2 domain containing 4A
Location	8p21.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20967, SH2A, PPP1R38
Ensembl gene	ENSG00000104611
Ensembl biotype	protein_coding
OMIM	614968
Entrez	63898

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 retained_intron

ENST00000265807, ENST00000518040, ENST00000518093, ENST00000519207, ENST00000522328, ENST00000523736, ENST00000903942, ENST00000903943, ENST00000962928

RefSeq mRNA: 5 — MANE Select: NM_022071 NM_001174159, NM_001174160, NM_001363110, NM_001363111, NM_022071

CCDS: CCDS55206, CCDS6009

Canonical transcript exons

ENST00000265807 — 10 exons

Exon	Start	End
ENSE00000888756	19364072	19364282
ENSE00000888757	19373530	19373660
ENSE00000888759	19393318	19393541
ENSE00000979994	19361203	19361314
ENSE00001040651	19319344	19319728
ENSE00001040655	19332955	19333114
ENSE00001040658	19357203	19357283
ENSE00001040659	19334686	19334857
ENSE00001342658	19313693	19313823
ENSE00001390050	19394550	19396218

Expression profiles

Bgee: expression breadth ubiquitous, 235 present calls, max score 95.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.6370 / max 443.1959, expressed in 1082 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87587	4.0402	862
87591	1.1349	533
87592	0.5943	323
87586	0.4847	297
87590	0.1674	77
87588	0.1581	62
87589	0.0437	8
87593	0.0135	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	95.01	gold quality
oocyte	CL:0000023	94.88	gold quality
calcaneal tendon	UBERON:0003701	90.85	gold quality
amniotic fluid	UBERON:0000173	89.83	gold quality
buccal mucosa cell	CL:0002336	88.77	gold quality
lower esophagus mucosa	UBERON:0035834	88.51	gold quality
oviduct epithelium	UBERON:0004804	88.46	gold quality
cervix squamous epithelium	UBERON:0006922	88.05	silver quality
esophagus mucosa	UBERON:0002469	87.80	gold quality
palpebral conjunctiva	UBERON:0001812	87.30	gold quality
left ovary	UBERON:0002119	86.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.45	gold quality
pylorus	UBERON:0001166	86.33	gold quality
ovary	UBERON:0000992	86.31	gold quality
parotid gland	UBERON:0001831	86.10	gold quality
right lobe of liver	UBERON:0001114	86.03	gold quality
epithelial cell of pancreas	CL:0000083	85.89	silver quality
nasal cavity epithelium	UBERON:0005384	85.81	gold quality
cardia of stomach	UBERON:0001162	85.69	gold quality
saliva-secreting gland	UBERON:0001044	85.53	gold quality
pharyngeal mucosa	UBERON:0000355	85.51	gold quality
liver	UBERON:0002107	85.24	gold quality
vena cava	UBERON:0004087	85.09	silver quality
minor salivary gland	UBERON:0001830	84.94	gold quality
islet of Langerhans	UBERON:0000006	84.33	gold quality
mouth mucosa	UBERON:0003729	84.19	gold quality
body of pancreas	UBERON:0001150	84.16	gold quality
tendon	UBERON:0000043	84.15	gold quality
body of tongue	UBERON:0011876	83.94	silver quality
pancreas	UBERON:0001264	83.93	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7051	yes	677.90
E-ANND-3	yes	10.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

63 targeting SH2D4A, 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-4283	100.00	66.42	2097
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-605-3P	99.88	69.22	1833
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-579-3P	99.86	71.66	3628
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-5007-3P	99.51	68.14	1242
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-6128	99.33	67.83	1581
HSA-MIR-4685-5P	99.25	65.99	1563

Literature-anchored findings (GeneRIF, showing 6)

• SH2D4A is dispensable for TCR signal transduction in T cells (PMID:18641339)
• SH2D4A inhibited cell proliferation by suppression of the ERalpha/PLC-gamma/PKC signaling pathway. (PMID:19712589)
• New evidence for SH2D4A involvement in hepatocellular carcinoma pathogenesis demonstrating for the first time its deregulation in cirrhotic nodules. (PMID:24315626)
• The chromosome 8p tumor suppressor genes SORBS3 and SH2D4A are physically and functionally linked and provide a molecular mechanism of inhibiting STAT3-mediated IL-6 signaling in hepatocellular carcinoma cells. (PMID:27311882)
• SH2D4A downregulation due to loss of chromosome 8p is associated with poor prognosis and low T cell infiltration in colorectal cancer. (PMID:34893760)
• SH2D4A inhibits esophageal squamous cell carcinoma progression through FAK/PI3K/AKT signaling pathway. (PMID:38043670)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sh2d4a	ENSDARG00000041378
mus_musculus	Sh2d4a	ENSMUSG00000053886
rattus_norvegicus	Sh2d4a	ENSRNOG00000013541
caenorhabditis_elegans		WBGENE00008733

Paralogs (4): SH2D2A (ENSG00000027869), SH2D4B (ENSG00000178217), SH2D7 (ENSG00000183476), HSH2D (ENSG00000196684)

Protein

Protein identifiers

SH2 domain-containing protein 4A — Q9H788 (reviewed: Q9H788)

Alternative names: Protein SH(2)A, Protein phosphatase 1 regulatory subunit 38

All UniProt accessions (2): Q9H788, H0YAT1

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits estrogen-induced cell proliferation by competing with PLCG for binding to ESR1, blocking the effect of estrogen on PLCG and repressing estrogen-induced proliferation. May play a role in T-cell development and function.

Subunit / interactions. Interacts with ESR1.

Subcellular location. Cytoplasm.

Tissue specificity. Ubiquitously expressed. Aberrantly expressed in some cancers.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H788-1	1	yes
Q9H788-2	2

RefSeq proteins (5): NP_001167630, NP_001167631, NP_001350039, NP_001350040, NP_071354* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR036860	SH2_dom_sf	Homologous_superfamily

Pfam: PF00017

UniProt features (24 total): sequence conflict 7, modified residue 4, sequence variant 4, region of interest 4, compositionally biased region 2, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H788-F1	73.71	0.24

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 (4): 261, 315, 118, 124

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 75 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, chr8p21, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, TGACATY_UNKNOWN, TGGNNNNNNKCCAR_UNKNOWN, LIU_CMYB_TARGETS_UP, CUI_TCF21_TARGETS_2_DN, YNGTTNNNATT_UNKNOWN, MODULE_342, MASSARWEH_TAMOXIFEN_RESISTANCE_UP, GOMF_PHOSPHATASE_BINDING, GSE13762_CTRL_VS_125_VITAMIND_DAY5_DC_UP, FOXO3_01, DUTERTRE_ESTRADIOL_RESPONSE_24HR_DN, CHYLA_CBFA2T3_TARGETS_DN

GO Biological Process (0):

GO Molecular Function (2): phosphatase binding (GO:0019902), protein binding (GO:0005515)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
enzyme binding	1
binding	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

548 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH2D4A	CCDC15	Q0P6D6	557
SH2D4A	MTHFSD	Q2M296	511
SH2D4A	KRTAP27-1	Q3LI81	507
SH2D4A	ABLIM3	O94929	462
SH2D4A	CCDC25	Q86WR0	453
SH2D4A	GLT6D1	Q7Z4J2	433
SH2D4A	DAGLB	Q8NCG7	429
SH2D4A	SCML2	Q9UQR0	414
SH2D4A	ADAM22	Q9P0K1	413
SH2D4A	PLPBP	O94903	409
SH2D4A	SPATC1	Q76KD6	406
SH2D4A	AUTS2	Q8WXX7	406
SH2D4A	NFIB	O00712	401
SH2D4A	SORBS3	O60504	400
SH2D4A	IFI30	P13284	393

IntAct

343 interactions, top by confidence:

A	B	Type	Score
PPP1CB	SH2D4A	psi-mi:“MI:0915”(physical association)	0.960
SH2D4A	PPP1CB	psi-mi:“MI:0915”(physical association)	0.960
HCLS1	SH2D4A	psi-mi:“MI:0915”(physical association)	0.830
SH2D4A	HCLS1	psi-mi:“MI:0915”(physical association)	0.830
SH2D4A	LDOC1	psi-mi:“MI:0915”(physical association)	0.780
TFIP11	SH2D4A	psi-mi:“MI:0915”(physical association)	0.780
LDOC1	SH2D4A	psi-mi:“MI:0915”(physical association)	0.780
SH2D4A	TFIP11	psi-mi:“MI:0915”(physical association)	0.780
SH2D4A	DBNL	psi-mi:“MI:0915”(physical association)	0.760
DBNL	SH2D4A	psi-mi:“MI:0915”(physical association)	0.760
PPP1CB	CCDC85C	psi-mi:“MI:0914”(association)	0.750
PPP1CB	CCDC85C	psi-mi:“MI:2364”(proximity)	0.750
SH2D4A	FSD2	psi-mi:“MI:0915”(physical association)	0.720
NECAB2	SH2D4A	psi-mi:“MI:0915”(physical association)	0.720
SORBS3	SH2D4A	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (180): SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), SH2D4A (Two-hybrid)

ESM2 similar proteins: A0JP43, A2AHC3, A2RRS8, A2VCV0, A4FU69, A4IG55, A5WUN7, A8T6P4, D3Z6S9, D3Z8E6, D4AEC2, E7F7X0, F7EC58, G3UZ78, Q06190, Q08AD1, Q2MJV9, Q3KQW7, Q3UH68, Q3UMB5, Q3V036, Q5SUV2, Q5T5Y3, Q5ZM60, Q640L3, Q640U0, Q66H73, Q69CM7, Q6AYC8, Q6IRN6, Q6PG04, Q6Q759, Q76LL6, Q76N89, Q7L0X2, Q80VH0, Q8C1B1, Q8C627, Q8CCG4, Q8CDN1

Diamond homologs: A6NKC9, A6X942, G5ECJ6, O08908, O88834, P03949, P46109, P47941, Q00655, Q08012, Q08CX2, Q56A36, Q5SQS7, Q5U2U2, Q6AYC8, Q6VYH9, Q6YKA8, Q8BI17, Q8UUU2, Q96JZ2, Q9D7V1, Q9H788, Q9NP31, Q9QXK9, P00519, P00520, P00521, P10447, P20936, P29353, P32577, P41239, P41240, P41241, P42684, P50904, P98083, Q03160, Q0IIE2, Q0VBZ0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 63 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.

GO biological processes:

GO term	Partners	Fold	FDR
endocytosis	6	10.6×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	82
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1912 predictions. Top by Δscore:

Variant	Effect	Δscore
8:19332951:GCAG:G	acceptor_loss	1.0000
8:19332952:CAG:C	acceptor_gain	1.0000
8:19332952:CAGAG:C	acceptor_loss	1.0000
8:19332953:A:AG	acceptor_gain	1.0000
8:19332953:AGA:A	acceptor_gain	1.0000
8:19332954:G:A	acceptor_loss	1.0000
8:19332954:G:GG	acceptor_gain	1.0000
8:19332954:GA:G	acceptor_gain	1.0000
8:19332954:GAG:G	acceptor_gain	1.0000
8:19332954:GAGA:G	acceptor_gain	1.0000
8:19332954:GAGAA:G	acceptor_gain	1.0000
8:19334684:A:AG	acceptor_gain	1.0000
8:19334685:G:GG	acceptor_gain	1.0000
8:19334685:GAA:G	acceptor_gain	1.0000
8:19334685:GAAAA:G	acceptor_gain	1.0000
8:19334856:GA:G	donor_gain	1.0000
8:19334858:G:GG	donor_gain	1.0000
8:19357201:A:AG	acceptor_gain	1.0000
8:19357202:G:GG	acceptor_gain	1.0000
8:19361185:T:TA	acceptor_gain	1.0000
8:19361190:T:A	acceptor_gain	1.0000
8:19361197:A:AG	acceptor_gain	1.0000
8:19361198:A:G	acceptor_gain	1.0000
8:19361200:C:G	acceptor_gain	1.0000
8:19361200:CA:C	acceptor_loss	1.0000
8:19361201:A:AG	acceptor_gain	1.0000
8:19361202:G:GG	acceptor_gain	1.0000
8:19361202:GA:G	acceptor_gain	1.0000
8:19361202:GAA:G	acceptor_gain	1.0000
8:19361202:GAAGA:G	acceptor_gain	1.0000

AlphaMissense

2975 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:19319603:T:C	L19P	0.997
8:19319643:A:C	R32S	0.997
8:19319643:A:T	R32S	0.997
8:19319627:T:A	L27Q	0.995
8:19373651:T:A	W347R	0.995
8:19373651:T:C	W347R	0.995
8:19319639:T:C	M31T	0.994
8:19332975:T:A	W68R	0.994
8:19332975:T:C	W68R	0.994
8:19373655:T:C	F348S	0.994
8:19393377:T:C	F370L	0.994
8:19393379:T:A	F370L	0.994
8:19393379:T:G	F370L	0.994
8:19319642:G:C	R32T	0.993
8:19319642:G:T	R32I	0.993
8:19319657:G:C	R37P	0.993
8:19319603:T:A	L19H	0.992
8:19319627:T:C	L27P	0.992
8:19319660:G:C	R38P	0.992
8:19393381:T:C	L371P	0.992
8:19393387:G:C	R373P	0.992
8:19319591:T:C	L15P	0.991
8:19319629:T:C	F28L	0.991
8:19319631:C:A	F28L	0.991
8:19319631:C:G	F28L	0.991
8:19373654:T:C	F348L	0.990
8:19373656:C:A	F348L	0.990
8:19373656:C:G	F348L	0.990
8:19393417:T:C	L383P	0.990
8:19373589:T:C	F326S	0.989

dbSNP variants (sampled 300 via entrez): RS1000023311 (8:19358028 C>T), RS1000066635 (8:19325164 C>G,T), RS1000102284 (8:19372113 T>A,C), RS1000116563 (8:19336522 G>T), RS1000119106 (8:19381433 G>T), RS1000173581 (8:19328459 C>T), RS1000202199 (8:19351376 G>T), RS1000232268 (8:19328372 T>A,C), RS1000243211 (8:19396107 C>A), RS1000253901 (8:19364103 A>C,T), RS1000268083 (8:19318825 A>G), RS1000272883 (8:19387610 G>T), RS1000290728 (8:19390414 A>G), RS1000413393 (8:19368630 T>A), RS1000458405 (8:19331283 A>G)

Disease associations

OMIM: gene MIM:614968 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002361_4	Smooth-surface caries	7.000000e-06
GCST002382_2	Urinary albumin excretion rate in type 1 diabetes	4.000000e-06
GCST002829_26	Urate levels in overweight individuals	1.000000e-06
GCST011154_8	Fasting plasma glucose	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005667	urinary albumin excretion rate
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	increases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
mercuric bromide	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
incobotulinumtoxinA	increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Calcitriol	increases expression, affects cotreatment	1
Dexamethasone	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Testosterone	affects cotreatment, increases expression, decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2F6	Abcam HeLa SH2D4A KO	Cancer cell line	Female

Clinical trials (associated diseases)

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