FAM3A

Summary

FAM3A (FAM3 metabolism regulating signaling molecule A, HGNC:13749) is a protein-coding gene on chromosome Xq28, encoding Protein FAM3A (P98173). May act as a defensin against invading fungal microorganisms.

This gene encodes a cytokine-like protein. The expression of this gene may be regulated by peroxisome proliferator-activated receptor gamma, and the encoded protein may be involved in the regulation of glucose and lipid metabolism. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 60343 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 60 total — 1 pathogenic
• MANE Select transcript: NM_021806

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13749
Approved symbol	FAM3A
Name	FAM3 metabolism regulating signaling molecule A
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	DXS560S, 2-19, XAP-7
Ensembl gene	ENSG00000071889
Ensembl biotype	protein_coding
OMIM	300492
Entrez	60343

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 24 protein_coding, 8 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000322269, ENST00000359889, ENST00000369641, ENST00000369643, ENST00000393572, ENST00000412894, ENST00000416319, ENST00000419205, ENST00000421517, ENST00000426266, ENST00000433619, ENST00000434658, ENST00000440318, ENST00000442929, ENST00000447601, ENST00000449971, ENST00000457212, ENST00000475657, ENST00000492763, ENST00000497506, ENST00000612856, ENST00000621967, ENST00000858755, ENST00000858756, ENST00000858757, ENST00000858758, ENST00000858759, ENST00000858760, ENST00000858761, ENST00000858762, ENST00000858763, ENST00000938531, ENST00000959364, ENST00000959365, ENST00000959366, ENST00000959367, ENST00000959368

RefSeq mRNA: 7 — MANE Select: NM_021806 NM_001171132, NM_001171133, NM_001171134, NM_001282311, NM_001282312, NM_001363822, NM_021806

CCDS: CCDS35453, CCDS55542, CCDS55543, CCDS76060, CCDS87800

Canonical transcript exons

ENST00000447601 — 9 exons

Exon	Start	End
ENSE00001946741	154515760	154516232
ENSE00003476225	154511848	154511871
ENSE00003608059	154508289	154508347
ENSE00003624095	154508474	154508597
ENSE00003631195	154507811	154507861
ENSE00003643891	154507203	154507329
ENSE00003648699	154506171	154506906
ENSE00003734672	154512823	154512936
ENSE00003789744	154507406	154507490

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 96.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.1297 / max 130.9571, expressed in 1816 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
201039	20.9930	1813
201038	3.1367	1402

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	96.52	gold quality
apex of heart	UBERON:0002098	96.43	gold quality
left ovary	UBERON:0002119	95.57	gold quality
adenohypophysis	UBERON:0002196	95.41	gold quality
right ovary	UBERON:0002118	95.27	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.19	gold quality
mucosa of stomach	UBERON:0001199	95.00	gold quality
mucosa of transverse colon	UBERON:0004991	94.88	gold quality
endocervix	UBERON:0000458	94.78	gold quality
left lobe of thyroid gland	UBERON:0001120	94.48	gold quality
right lobe of liver	UBERON:0001114	94.45	gold quality
body of pancreas	UBERON:0001150	94.33	gold quality
right lobe of thyroid gland	UBERON:0001119	94.30	gold quality
pituitary gland	UBERON:0000007	94.11	gold quality
right atrium auricular region	UBERON:0006631	94.09	gold quality
ectocervix	UBERON:0012249	93.96	gold quality
spinal cord	UBERON:0002240	93.46	gold quality
body of stomach	UBERON:0001161	93.43	gold quality
left adrenal gland cortex	UBERON:0035825	93.43	gold quality
transverse colon	UBERON:0001157	93.40	gold quality
body of uterus	UBERON:0009853	93.40	gold quality
right frontal lobe	UBERON:0002810	93.24	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.23	gold quality
thyroid gland	UBERON:0002046	93.18	gold quality
right uterine tube	UBERON:0001302	93.05	gold quality
left uterine tube	UBERON:0001303	93.03	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.01	gold quality
left adrenal gland	UBERON:0001234	92.97	gold quality
metanephros cortex	UBERON:0010533	92.87	gold quality
lower esophagus	UBERON:0013473	92.85	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.25
E-HCAD-5	no	2.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARA, PPARG

miRNA regulators (miRDB)

16 targeting FAM3A, 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-6778-3P	99.96	67.29	2693
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-3155A	98.16	66.09	965
HSA-MIR-3155B	98.16	66.09	965
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-7154-3P	97.65	65.02	985
HSA-MIR-6890-3P	97.50	65.71	997
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-6762-5P	96.55	64.62	972
HSA-MIR-6845-5P	96.55	64.65	969

Literature-anchored findings (GeneRIF, showing 12)

• Expressed prominently in the vascular endothelium, particularly capillaries, also in islets of Langerhans. (PMID:12160727)
• In the present study, we report a putative human homologue of the antimicrobial Drosophila-derived drosomycin, designated drosomycin-like defensin (DLD), with specific antifungal activity. (PMID:18212107)
• Upregulation of FAM3A by PPARgamma activation is correlated with increased pAkt level in liver cells (PMID:23562554)
• FAM3A plays crucial roles in the regulation of glucose and lipid metabolism in the liver, where it activates the PI3K-Akt signaling pathway by way of a Ca(2+) /CaM-dependent mechanism (PMID:24806753)
• These results suggest that C/EBPbeta plays an important role in regulating FAM3A promoter activity and FAM3A inhibits adipocyte differentiation. (PMID:27688071)
• Fam3A may regulate high glucose-induced reactive oxygen species production in HUVECs via the p38 MAPK signaling pathway. (PMID:29532774)
• our data demonstrate that FAM3A positively regulates angiogenesis through activation of VEGFA transcription, suggesting that FAM3A may constitute a novel molecular therapeutic target for ischaemic vascular disease. (PMID:31000420)
• In this case prenatal ultrasound images were suggestive of a serious but non-lethal skeletal dysplasia. Due to the uncertain prognosis the parents were offered Whole Exome Sequencing (WES), which identified a specific gene mutation in the FAMIIIa gene (PMID:31910817)
• FAM3A mediates the phenotypic switch of human aortic smooth muscle cells stimulated with oxidised low-density lipoprotein by influencing the PI3K-AKT pathway. (PMID:37474885)
• FAM3A plays a key role in protecting against tubular cell pyroptosis and acute kidney injury. (PMID:38875957)
• PANX1-mediated ATP release confers FAM3A’s suppression effects on hepatic gluconeogenesis and lipogenesis. (PMID:38937853)
• Circulating extracellular vesicle-derived miR-1299 disrupts hepatic glucose homeostasis by targeting the STAT3/FAM3A axis in gestational diabetes mellitus. (PMID:39182087)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fam3a	ENSDARG00000070675
mus_musculus	Fam3a	ENSMUSG00000031399
rattus_norvegicus	Fam3a	ENSRNOG00000060623
caenorhabditis_elegans		WBGENE00019786

Paralogs (3): FAM3B (ENSG00000183844), FAM3C (ENSG00000196937), FAM3D (ENSG00000198643)

Protein

Protein identifiers

Protein FAM3A — P98173 (reviewed: P98173)

Alternative names: Cytokine-like protein 2-19

All UniProt accessions (10): P98173, A6QRH7, A6QRH8, D3DWX8, F8WB47, F8WD39, F8WEM7, F8WEW8, Q5HY75, Q9BU27

UniProt curated annotations — full annotation on UniProt →

Function. May act as a defensin against invading fungal microorganisms.

Subcellular location. Secreted.

Tissue specificity. In similar amounts in testis, pancreas, adrenal, placenta, brain, fetal brain, liver, kidney, skeletal muscle and heart.

Similarity. Belongs to the FAM3 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P98173-1	1	yes
P98173-2	2
P98173-3	3

RefSeq proteins (7): NP_001164603, NP_001164604, NP_001164605, NP_001269240, NP_001269241, NP_001350751, NP_068578* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR039220	FAM3	Family
IPR039475	ILEI_FAM3C	Domain
IPR039477	ILEI/PANDER_dom	Domain

Pfam: PF15711

UniProt features (9 total): disulfide bond 2, splice variant 2, sequence variant 2, signal peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P98173-F1	89.05	0.74

Functional residue map

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

Disulfide bonds (2): 59–87, 65–222

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 145 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_INSULIN_SECRETION, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_CELL_CELL_SIGNALING

GO Biological Process (10): glucose metabolic process (GO:0006006), ATP biosynthetic process (GO:0006754), mitochondrion organization (GO:0007005), response to glucose (GO:0009749), gene expression (GO:0010467), antifungal humoral response (GO:0019732), insulin secretion (GO:0030073), calcium ion homeostasis (GO:0055074), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), negative regulation of antifungal innate immune response (GO:1905035)

GO Molecular Function (2): carbohydrate binding (GO:0030246), protein binding (GO:0005515)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
antimicrobial humoral response	2
binding	2
cellular anatomical structure	2
hexose metabolic process	1
purine ribonucleotide biosynthetic process	1
purine ribonucleoside triphosphate biosynthetic process	1
ATP metabolic process	1
organelle organization	1
response to hexose	1
macromolecule biosynthetic process	1
defense response to fungus	1
protein secretion	1
peptide hormone secretion	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
negative regulation of innate immune response	1
antifungal innate immune response	1
regulation of antifungal innate immune response	1

Protein interactions and networks

STRING

368 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FAM3A	C3orf18	Q9UK00	492
FAM3A	ABHD1	Q96SE0	478
FAM3A	UNC45A	Q9H3U1	447
FAM3A	HEATR1	Q9H583	443
FAM3A	UNC45B	Q8IWX7	426
FAM3A	FAM20B	O75063	348
FAM3A	P0DMU3	P0DMU3	331
FAM3A	CCDC22	O60826	328
FAM3A	NXPE2	Q96DL1	290
FAM3A	TXNDC15	Q96J42	286
FAM3A	GMPPA	Q96IJ6	284
FAM3A	KARS1	Q15046	274
FAM3A	NFE2	Q16621	270
FAM3A	PYURF	Q96I23	248
FAM3A	SH2D5	Q6ZV89	247

IntAct

13 interactions, top by confidence:

A	B	Type	Score
FAM3A	CREB3	psi-mi:“MI:0915”(physical association)	0.370
PACRGL	FAM3A	psi-mi:“MI:0915”(physical association)	0.370
ORF47	ZZEF1	psi-mi:“MI:0914”(association)	0.350
B3GNT2	NDUFA10	psi-mi:“MI:0914”(association)	0.350
B3GNT2	PDLIM1	psi-mi:“MI:0914”(association)	0.350
FAM3A	NMU	psi-mi:“MI:0914”(association)	0.350
B3GNT2	FAM3A	psi-mi:“MI:0914”(association)	0.350
SLC30A7	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC3A1	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC47A1	PLOD2	psi-mi:“MI:0914”(association)	0.350
SLC9A9	PODXL	psi-mi:“MI:0914”(association)	0.350

BioGRID (30): FAM3A (Two-hybrid), FAM3A (Two-hybrid), CLEC7A (Two-hybrid), MAL2 (Two-hybrid), FAM3A (Affinity Capture-MS), FAM3A (Two-hybrid), FAM3A (Two-hybrid), FAM3A (Affinity Capture-MS), FAM3A (Affinity Capture-MS), FAM3A (Affinity Capture-MS), FAM3A (Affinity Capture-RNA), FAM3A (Affinity Capture-MS), NMU (Affinity Capture-MS), HS6ST2 (Affinity Capture-MS), FAM3A (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GVV1, A2AFS3, A4IFL2, B1AZA5, D4ABL6, E9PV86, M0R7X9, O73612, P01134, P01135, P01344, P07456, P10764, P23695, P33717, P48030, P51459, P52799, P52800, P55244, P98135, P98173, Q06922, Q0VBP7, Q17QD6, Q2YDG0, Q3KRC4, Q3SXP7, Q3ZBS2, Q4V7F2, Q5EA46, Q5R5C3, Q6DN14, Q6NW40, Q6ZN54, Q7Z5A7, Q7Z6G3, Q7Z6J6, Q8K3J9, Q8NBT3

Diamond homologs: A5PKI3, B0BLS9, P58499, P97805, P98173, Q5R5C3, Q6GQC1, Q7ZYY4, Q810F4, Q8BI06, Q8WUJ3, Q91VU0, Q92520, Q96BQ1, Q9D309, Q9D8T0, Q5EAB6, Q5RCB9, Q5XIN7, Q8WZA1, Q91X88, A3KPQ7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	11
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
58008	GRCh38/hg38 Xq28(chrX:153296806-155699618)x1	Pathogenic

SpliceAI

1702 predictions. Top by Δscore:

Variant	Effect	Δscore
X:154506903:CGTG:C	acceptor_gain	1.0000
X:154506904:GTG:G	acceptor_gain	1.0000
X:154506905:TG:T	acceptor_gain	1.0000
X:154506905:TGCTG:T	acceptor_loss	1.0000
X:154506906:GCTGT:G	acceptor_loss	1.0000
X:154506907:C:CC	acceptor_gain	1.0000
X:154506907:CT:C	acceptor_loss	1.0000
X:154506909:G:C	acceptor_gain	1.0000
X:154507199:ATACC:A	donor_loss	1.0000
X:154507200:TA:T	donor_loss	1.0000
X:154507201:A:T	donor_loss	1.0000
X:154507202:CCTG:C	donor_gain	1.0000
X:154507254:G:C	donor_gain	1.0000
X:154507325:TCATC:T	acceptor_gain	1.0000
X:154507326:CATC:C	acceptor_gain	1.0000
X:154507326:CATCC:C	acceptor_gain	1.0000
X:154507328:TC:T	acceptor_gain	1.0000
X:154507329:CC:C	acceptor_gain	1.0000
X:154507330:C:CC	acceptor_gain	1.0000
X:154507330:C:CG	acceptor_loss	1.0000
X:154507400:ACCT:A	donor_loss	1.0000
X:154507403:TA:T	donor_loss	1.0000
X:154507404:A:AC	donor_gain	1.0000
X:154507404:AC:A	donor_loss	1.0000
X:154507405:C:CC	donor_gain	1.0000
X:154507486:GACAT:G	acceptor_gain	1.0000
X:154507488:CAT:C	acceptor_gain	1.0000
X:154507489:AT:A	acceptor_gain	1.0000
X:154507490:TCTG:T	acceptor_loss	1.0000
X:154507491:C:CA	acceptor_loss	1.0000

AlphaMissense

1523 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:154506865:C:A	W213C	1.000
X:154506865:C:G	W213C	1.000
X:154506867:A:G	W213R	1.000
X:154506867:A:T	W213R	1.000
X:154506875:T:C	Y210C	1.000
X:154507251:C:A	W183C	1.000
X:154507251:C:G	W183C	1.000
X:154507253:A:G	W183R	1.000
X:154507253:A:T	W183R	1.000
X:154508312:C:T	G104E	1.000
X:154508519:C:T	G77E	1.000
X:154508520:C:A	G77W	1.000
X:154506839:C:G	C222S	0.999
X:154506840:A:G	C222R	0.999
X:154506840:A:T	C222S	0.999
X:154506863:G:T	P214H	0.999
X:154506876:A:G	Y210H	0.999
X:154507243:A:T	V186D	0.999
X:154507246:A:G	F185S	0.999
X:154507254:G:C	S182R	0.999
X:154507254:G:T	S182R	0.999
X:154507256:T:G	S182R	0.999
X:154507258:T:A	D181V	0.999
X:154507261:C:G	R180P	0.999
X:154507263:G:C	F179L	0.999
X:154507263:G:T	F179L	0.999
X:154507265:A:G	F179L	0.999
X:154507287:G:C	S171R	0.999
X:154507287:G:T	S171R	0.999
X:154507289:T:G	S171R	0.999

dbSNP variants (sampled 300 via entrez): RS1000343705 (X:154515305 C>T), RS1001789813 (X:154506474 G>A), RS1002018459 (X:154513561 C>T), RS1002516830 (X:154514075 G>A), RS1002679643 (X:154509568 A>G), RS1002831992 (X:154510196 G>A), RS1002950949 (X:154517912 G>A), RS1003465607 (X:154505743 G>A), RS1003787848 (X:154511965 G>A,C), RS1004099446 (X:154511567 G>C), RS1004501440 (X:154505908 A>T), RS1004579687 (X:154506017 C>A,T), RS1005040791 (X:154511985 G>A,T), RS1005706335 (X:154516773 C>T), RS1006694169 (X:154507117 C>T)

Disease associations

OMIM: gene MIM:300492 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001873_9	Red blood cell traits	4.000000e-14
GCST003122_2	Hemoglobin levels	3.000000e-11
GCST90002381_505	Eosinophil count	2.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0007629	hemoglobin A1 measurement
EFO:0004842	eosinophil count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
bisphenol A	decreases expression	1
potassium chromate(VI)	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Hydralazine	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Selenium	affects cotreatment, decreases expression, increases expression	1
Smoke	decreases expression	1
Valproic Acid	affects cotreatment, increases expression	1
Vitamin E	affects cotreatment, decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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