FAM13A

Summary

FAM13A (family with sequence similarity 13 member A, HGNC:19367) is a protein-coding gene on chromosome 4q22.1, encoding Protein FAM13A (O94988).

Predicted to enable GTPase activator activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Predicted to be located in cytosol. Implicated in chronic obstructive pulmonary disease.

Source: NCBI Gene 10144 — RefSeq curated summary.

At a glance

• GWAS associations: 293
• Clinical variants (ClinVar): 177 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 20
• MANE Select transcript: NM_014883

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19367
Approved symbol	FAM13A
Name	family with sequence similarity 13 member A
Location	4q22.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0914, ARHGAP48
Ensembl gene	ENSG00000138640
Ensembl biotype	protein_coding
OMIM	613299
Entrez	10144

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 14 protein_coding, 7 retained_intron, 3 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000264344, ENST00000395002, ENST00000502459, ENST00000502914, ENST00000503556, ENST00000504229, ENST00000504836, ENST00000506433, ENST00000506913, ENST00000507352, ENST00000508360, ENST00000508369, ENST00000509094, ENST00000509478, ENST00000511145, ENST00000511573, ENST00000511623, ENST00000511976, ENST00000512339, ENST00000513837, ENST00000515155, ENST00000515600, ENST00000889026, ENST00000933309, ENST00000933310, ENST00000953080, ENST00000953082

RefSeq mRNA: 5 — MANE Select: NM_014883 NM_001015045, NM_001265578, NM_001265579, NM_001265580, NM_014883

CCDS: CCDS34029, CCDS43251, CCDS58911, CCDS58912, CCDS58913

Canonical transcript exons

ENST00000264344 — 24 exons

Exon	Start	End
ENSE00002236950	89056938	89057185
ENSE00003475035	89029460	89029649
ENSE00003482194	88739030	88739125
ENSE00003482283	88749771	88749909
ENSE00003503639	88746932	88747015
ENSE00003504524	88750424	88750637
ENSE00003522112	88990973	88991150
ENSE00003546108	88787753	88787932
ENSE00003556907	88781165	88781351
ENSE00003557014	88737472	88737555
ENSE00003564467	89020460	89020669
ENSE00003568754	88906379	88906462
ENSE00003570305	88732002	88732198
ENSE00003594761	88758754	88758901
ENSE00003607790	88805011	88805052
ENSE00003618972	88938088	88938241
ENSE00003622099	88748952	88749033
ENSE00003634676	88851020	88851183
ENSE00003637366	88731327	88731428
ENSE00003657681	88767553	88767595
ENSE00003685034	88747631	88747851
ENSE00003692910	88790586	88790627
ENSE00003694416	88767983	88768059
ENSE00003847952	88725960	88728659

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.2620 / max 556.9679, expressed in 1528 samples.

FANTOM5 promoters (22 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53136	6.3371	1255
53123	5.0978	819
53124	3.2596	867
53135	0.6758	367
53126	0.4671	199
53114	0.4656	110
53115	0.1766	67
53119	0.1362	60
53125	0.1045	32
53116	0.1017	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.95	gold quality
oocyte	CL:0000023	99.88	gold quality
jejunal mucosa	UBERON:0000399	99.35	gold quality
pigmented layer of retina	UBERON:0001782	98.61	gold quality
retina	UBERON:0000966	98.59	gold quality
bronchial epithelial cell	CL:0002328	98.05	gold quality
choroid plexus epithelium	UBERON:0003911	98.00	gold quality
parietal pleura	UBERON:0002400	97.93	gold quality
parotid gland	UBERON:0001831	97.87	gold quality
hair follicle	UBERON:0002073	97.36	gold quality
renal medulla	UBERON:0000362	97.28	gold quality
duodenum	UBERON:0002114	97.17	gold quality
middle temporal gyrus	UBERON:0002771	97.13	gold quality
pleura	UBERON:0000977	96.98	gold quality
germinal epithelium of ovary	UBERON:0001304	96.98	gold quality
endothelial cell	CL:0000115	96.97	gold quality
placenta	UBERON:0001987	96.66	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.64	gold quality
epithelium of bronchus	UBERON:0002031	96.60	gold quality
skin of hip	UBERON:0001554	96.50	gold quality
jejunum	UBERON:0002115	96.48	gold quality
bronchus	UBERON:0002185	96.43	gold quality
calcaneal tendon	UBERON:0003701	96.06	gold quality
caput epididymis	UBERON:0004358	95.95	gold quality
ventricular zone	UBERON:0003053	95.94	gold quality
tibia	UBERON:0000979	95.80	gold quality
visceral pleura	UBERON:0002401	95.76	gold quality
nephron tubule	UBERON:0001231	95.75	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.44	gold quality
thoracic mammary gland	UBERON:0005200	95.29	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-112	no	2.86
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

130 targeting FAM13A, 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-6867-5P	100.00	82.21	3464
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-4671-3P	99.88	72.46	1045

Literature-anchored findings (GeneRIF, showing 37)

• A new susceptibility locus at 4q22.1 in FAM13A and replicated this association in one case-control group (n = 1,006) and two family-based cohorts. (PMID:20173748)
• these results support that FAM13A rs2869967 and XRCC5 rs3821104 are associated with COPD in Chinese Han population. (PMID:22027142)
• FAM13A1 is one of the top hub genes associated with human Treg suppressor function. See Table 1 of the publication. (PMID:23169000)
• the FAM13A locus might be a contributor to chronic obstructive pulmonary disease susceptibility in Chinese Han population. (PMID:23891779)
• Haplotypes carrying major alleles of rs7671167 (C) of FAM13A had a protective effect on lung function amongst South Indian male smokers with COPD. (PMID:24587150)
• CT quantitative analysis of lung parenchyma is very well correlated with COPD candidate gene FAM13A. (PMID:24651745)
• This review gives a brief summary of the current knowledge of FAM13A, and demonstrates the necessity to resolve its biological function besides its well accepted genetic contribution. (PMID:25163686)
• Data indicate that the FAM13A protein CTGA haplotypes interacted with heavy smoking to affect the risk of reduced pulmonary function. (PMID:25608829)
• Fam13a may contribute to human lung diseases. (PMID:25609086)
• This study confirms that the IREB2 variants contribute to an increased risk of lung cancer, whereas FAM13A predisposes to increased susceptibility to chronic obstructive pulmonary disease. (PMID:26310313)
• FAM13A - candidate gene for Chronic Obstructive Pulmonary Disease identified by Genome-wide association studies. (PMID:26527870)
• this study shows that FAM13A confers a risk for airway obstruction in general that is not driven exclusively by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease (PMID:27612410)
• FAM13A gene polymorphism showed a significant association with the susceptibility to idiopathic pulmonary fibrosis, with severity of lung function impairment and with poor prognosis. (PMID:28137485)
• noncoding FAM13A polymorphisms were correlated with gene expression levels, and thus were probably in linkage disequilibrium with genetic loci that regulated the expression of FAM13A (PMID:28569593)
• Data show that FAM13A is a modifier gene of Cystic Fibrosis lung phenotype regulating RhoA activity, actin cytoskeleton dynamics and epithelial-mesenchymal transition. (PMID:29239766)
• Gene expression and adipocyte functional studies support the notion that FAM13A and POM121C control adipocyte lipolysis and adipogenesis, respectively, and might thereby be involved in genetic control of systemic insulin sensitivity (PMID:29487953)
• The rs2609255 in FAM13A gene may modify silicosis susceptibility in the Chinese population. (PMID:29621588)
• rs17014601 in FAM13A was significantly associated with COPD in the additive (odds ratio [OR]=1.36, 95% confidence interval [CI]: 1.11-1.67, P=0.003), heterozygote (OR=1.76, 95% CI: 1.33-2.32, P=0.0001), and dominant (OR=1.67, 95% CI: 1.28-2.18, P=0.0001) models. Stratified analyses indicated that the risk was higher in never smokers. (PMID:29872291)
• rs2013701 as a functional variant likely to contribute to the development of COPD (PMID:30079747)
• Our results suggest that FAM13A is dispensable for adipose development and insulin sensitivity. Yet the expression of FAM13A needs to be tightly controlled in adipose precursor cells for their proper survival and downstream adipogenesis. These data provide novel insights into the link between FAM13A and obesity. (PMID:30301961)
• High expression of FAM13A may be associated with an increased risk of liver cirrhosis. Risk of liver cirrhosis was significantly associated with G/A-G/G genotype of rs3017895. (PMID:30604588)
• Role of Polymorphisms of FAM13A, PHLDB1, and CYP24A1 in Breast Cancer Risk. (PMID:31215377)
• Variant genotypes of rs9224 in the FAM13A 3’UTR may modify Lung squamous carcinoma (LUSQ) susceptibility by affecting the binding of miRNA-22-5p and predict a poor prognosis of patients with LUSQ. (PMID:31539274)
• Loss of Family with Sequence Similarity 13, Member A Exacerbates Pulmonary Fibrosis Potentially by Promoting Epithelial to Mesenchymal Transition. (PMID:32029695)
• GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution. (PMID:32193374)
• Respiratory traits and coal workers’ pneumoconiosis: Mendelian randomisation and association analysis. (PMID:33097673)
• FAM13A as potential therapeutic target in modulating TGF-beta-induced airway tissue remodeling in COPD. (PMID:34105356)
• Connecting COPD GWAS Genes: FAM13A Controls TGFbeta2 Secretion by Modulating AP-3 Transport. (PMID:34166600)
• Family with sequence similarity 13 member A mediates TGF-beta1-induced EMT in small airway epithelium of patients with chronic obstructive pulmonary disease. (PMID:34210319)
• miR30a5p induces the adipogenic differentiation of bone marrow mesenchymal stem cells by targeting FAM13A/Wnt/betacatenin signaling in aplastic anemia. (PMID:34821370)
• Association of a FAM13A variant with interstitial lung disease in Japanese rheumatoid arthritis. (PMID:36717188)
• The Influence of FAM13A and PPAR-gamma2 Gene Polymorphisms on the Metabolic State of Postmenopausal Women. (PMID:37107672)
• Single Nucleotide Polymorphisms of FAM13A Gene in Chronic Obstructive Pulmonary Disease-A Case Control Study in Vietnam. (PMID:37366807)
• FAM13A polymorphisms are associated with a specific susceptibility to clinical progression of oral cancer in alcohol drinkers. (PMID:37391706)
• FAM13A regulates cellular senescence marker p21 and mitochondrial reactive oxygen species production in airway epithelial cells. (PMID:37605846)
• Association of family sequence similarity gene 13A gene polymorphism and interstitial lung disease susceptibility: A systematic review and meta-analysis. (PMID:37786320)
• The FAM13A Long Isoform Regulates Cilia Movement and Coordination in Airway Mucociliary Transport. (PMID:38691660)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fam13a	ENSDARG00000075564
danio_rerio		ENSDARG00000116732
mus_musculus	Fam13a	ENSMUSG00000037709
rattus_norvegicus	Fam13a	ENSRNOG00000007947
drosophila_melanogaster	CG6424	FBGN0028494

Paralogs (2): FAM13B (ENSG00000031003), FAM13C (ENSG00000148541)

Protein

Protein identifiers

Protein FAM13A — O94988 (reviewed: O94988)

All UniProt accessions (8): O94988, D6RCC1, D6RD35, D6RFM4, D6RGE4, D6RIY4, E9PGM7, Q6P521

UniProt curated annotations — full annotation on UniProt →

Tissue specificity. Isoform 1 is widely expressed, with highest expression in skeletal muscle, thymus, brain and lung. Isoform 3 is less abundant than isoform 1 and predominantly expressed in kidney, pancreas, liver, lung and thymus.

Similarity. Belongs to the FAM13 family.

Isoforms (5)

UniProt ID	Names	Canonical?
O94988-4	3, FAM13A1_v2	yes
O94988-1	1, FAM13A1_v1
O94988-3	2
O94988-5	4
O94988-6	5

RefSeq proteins (5): NP_001015045, NP_001252507, NP_001252508, NP_001252509, NP_055698* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR039102	FAM13	Family
IPR059029	FAM13A_dom	Domain

Pfam: PF00620, PF26116

UniProt features (31 total): splice variant 7, compositionally biased region 6, modified residue 5, region of interest 5, sequence conflict 2, coiled-coil region 2, chain 1, domain 1, site 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94988-F1	61.00	0.31

Functional residue map

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

Catalytic / active sites (1): 81 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Post-translational modifications (5): 345, 597, 617, 727, 732

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle

MSigDB gene sets: 254 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, TGCACTT_MIR519C_MIR519B_MIR519A, MENSE_HYPOXIA_UP, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, MORF_RAD51L3, BOYAULT_LIVER_CANCER_SUBCLASS_G12_DN, MODULE_379, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, MORF_PRKCA, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, GOZGIT_ESR1_TARGETS_UP, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, BASAKI_YBX1_TARGETS_DN, chr4q22

GO Biological Process (2): signal transduction (GO:0007165), regulation of small GTPase mediated signal transduction (GO:0051056)

GO Molecular Function (1): GTPase activator activity (GO:0005096)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

748 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FAM13A	IREB2	P48200	869
FAM13A	HHIP	Q96QV1	851
FAM13A	CHRNA3	P32297	720
FAM13A	GSTCD	Q8NEC7	706
FAM13A	CHRNA5	P30532	641
FAM13A	TRPV4	Q9HBA0	640
FAM13A	MMP12	P39900	626
FAM13A	RIN3	Q8TB24	615
FAM13A	SERPINA1	P01009	615
FAM13A	THSD4	Q6ZMP0	601
FAM13A	SOD3	P08294	597
FAM13A	PID1	Q7Z2X4	582
FAM13A	SERPINE2	P07093	580
FAM13A	HERC3	Q15034	575
FAM13A	ATP11A	P98196	574

IntAct

40 interactions, top by confidence:

A	B	Type	Score
MYO6	GIPC1	psi-mi:“MI:0914”(association)	0.690
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
PCNA	POM121C	psi-mi:“MI:0914”(association)	0.550
YWHAZ	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
PPP2R5A	AXIN1	psi-mi:“MI:0914”(association)	0.530
FAM13A	SHANK3	psi-mi:“MI:0915”(physical association)	0.370
Ppp2r1a	CCHCR1	psi-mi:“MI:0914”(association)	0.350
RTEL1-TNFRSF6B	FAM13A	psi-mi:“MI:0914”(association)	0.350
PPP2R1A	INTS2	psi-mi:“MI:0914”(association)	0.350
ERP44	NRDC	psi-mi:“MI:0914”(association)	0.350
MPP1	DKC1	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
YWHAZ	SPEG	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
	AP3D1	psi-mi:“MI:0914”(association)	0.350
SFN	SHTN1	psi-mi:“MI:0914”(association)	0.350
YWHAH	SHTN1	psi-mi:“MI:0914”(association)	0.350
YWHAQ	SHTN1	psi-mi:“MI:0914”(association)	0.350
YWHAE	DEPDC5	psi-mi:“MI:0914”(association)	0.350
YWHAG	BRAF	psi-mi:“MI:0914”(association)	0.350
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
FAM13A	UNC119B	psi-mi:“MI:0914”(association)	0.350
AHCYL1	TRAF5	psi-mi:“MI:0914”(association)	0.350
TBCCD1	FAM13A	psi-mi:“MI:0914”(association)	0.350
AHCYL2	AHCYL1	psi-mi:“MI:0914”(association)	0.350
SLC4A7	SAP18	psi-mi:“MI:0914”(association)	0.350

BioGRID (42): FAM13A (Affinity Capture-MS), FAM13A (Affinity Capture-MS), FAM13A (Affinity Capture-MS), FAM13A (Affinity Capture-MS), FAM13A (Affinity Capture-MS), FAM13A (Affinity Capture-MS), UNC119 (Affinity Capture-MS), FAM13A (Affinity Capture-MS), FAM13A (Affinity Capture-RNA), FAM13A (Affinity Capture-RNA), FAM13A (FRET), AHCYL1 (Affinity Capture-MS), AHCYL2 (Affinity Capture-MS), PPP2CA (Affinity Capture-MS), PPP2R1A (Affinity Capture-MS)

ESM2 similar proteins: A0FIN4, A2VD01, A9ZLX4, D2HNW6, D4A7U2, O88974, O94988, P10914, P14316, P15314, P16236, P17433, P17947, P23570, P23906, P49140, Q00IB7, Q13506, Q13905, Q15047, Q1LY51, Q3B7M3, Q3SZP0, Q3TTA7, Q3UWM4, Q4V7W5, Q5HYC2, Q5RJA1, Q5XJV7, Q61122, Q62722, Q6A098, Q6AI12, Q6BDS1, Q6DFR2, Q6GQL0, Q6PKU1, Q6ZMT4, Q6ZNC4, Q80TJ7

Diamond homologs: A0A0G2JTR4, A2AB59, A2RUV4, A4IF90, A4II46, A6QNS3, A6X8Z5, A7E300, A7KAX9, A8WRJ2, B2RTY4, D3ZZN9, E7EZG2, E7F3F0, F1LXF1, O14559, O43182, O54834, O74360, O94988, P11274, P15882, P30337, P34288, P42331, P46941, P52757, P98171, Q03070, Q08DP6, Q10164, Q12979, Q13459, Q15311, Q17QN0, Q20498, Q2M1Z3, Q3UIA2, Q53QZ3, Q54FG5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FAM13A	“down-regulates activity”	RAC1	“gtpase-activating protein”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 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	152.3×	2e-12
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	134.3×	3e-12
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	134.3×	3e-12
Activation of BH3-only proteins	7	99.3×	2e-11
RHO GTPases activate PKNs	7	63.4×	4e-10
Intrinsic Pathway for Apoptosis	7	58.6×	7e-10
RAF activation	5	48.0×	6e-07
FOXO-mediated transcription	5	48.0×	6e-07

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	6	48.9×	9e-07
intracellular protein localization	8	18.6×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	124
Likely benign	10
Benign	7

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
14009	GRCh38/hg38 4q22.1(chr4:88504598-90127832)x3	Pathogenic
1699915	NC_000004.12:g.(?88928831)(88996847_?)del	Pathogenic
1710295	t(4;20)(q22.1;p12.2)	Pathogenic
4819274	Single allele	Likely pathogenic

SpliceAI

6416 predictions. Top by Δscore:

Variant	Effect	Δscore
4:88728655:CATTT:C	acceptor_gain	1.0000
4:88728657:TTT:T	acceptor_gain	1.0000
4:88731321:CACTA:C	donor_loss	1.0000
4:88731322:ACTAC:A	donor_loss	1.0000
4:88731324:TACCT:T	donor_loss	1.0000
4:88731326:CCT:C	donor_loss	1.0000
4:88731329:T:TA	donor_gain	1.0000
4:88731424:CAGGT:C	acceptor_gain	1.0000
4:88731425:AGGT:A	acceptor_gain	1.0000
4:88731426:GGT:G	acceptor_gain	1.0000
4:88731427:GT:G	acceptor_gain	1.0000
4:88731428:TCTAA:T	acceptor_loss	1.0000
4:88731429:C:CC	acceptor_gain	1.0000
4:88731430:T:G	acceptor_loss	1.0000
4:88731444:CAT:C	acceptor_gain	1.0000
4:88731446:T:C	acceptor_gain	1.0000
4:88731446:T:TC	acceptor_gain	1.0000
4:88732000:A:AC	donor_gain	1.0000
4:88732001:C:CC	donor_gain	1.0000
4:88732035:T:TA	donor_gain	1.0000
4:88739028:A:AC	donor_gain	1.0000
4:88739029:C:CC	donor_gain	1.0000
4:88739029:CA:C	donor_gain	1.0000
4:88739029:CAATG:C	donor_gain	1.0000
4:88739121:GTTAC:G	acceptor_gain	1.0000
4:88739122:TTAC:T	acceptor_gain	1.0000
4:88739123:TAC:T	acceptor_gain	1.0000
4:88739124:AC:A	acceptor_gain	1.0000
4:88739125:CC:C	acceptor_gain	1.0000
4:88739125:CCTGA:C	acceptor_loss	1.0000

AlphaMissense

6795 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:88728582:A:G	L1008P	0.999
4:88728588:A:G	L1006P	0.999
4:88731420:A:G	L951P	0.999
4:88739066:T:A	K842N	0.999
4:88739066:T:G	K842N	0.999
4:88739076:C:G	R839P	0.999
4:88739080:A:C	Y838D	0.999
4:88746963:A:G	L812P	0.999
4:88746975:A:G	L808P	0.999
4:88747796:G:C	S739R	0.999
4:88747796:G:T	S739R	0.999
4:88747798:T:G	S739R	0.999
4:88748978:A:G	L712P	0.999
4:88749032:G:T	P694H	0.999
4:88728570:A:G	L1012P	0.998
4:88728579:A:G	L1009P	0.998
4:88728596:C:A	K1003N	0.998
4:88728596:C:G	K1003N	0.998
4:88731408:A:G	L955P	0.998
4:88739067:T:A	K842I	0.998
4:88739068:T:C	K842E	0.998
4:88739070:A:T	V841D	0.998
4:88739073:A:G	L840P	0.998
4:88739080:A:G	Y838H	0.998
4:88746971:C:A	Q809H	0.998
4:88746971:C:G	Q809H	0.998
4:88747674:A:G	L780P	0.998
4:88747778:A:C	S745R	0.998
4:88747778:A:T	S745R	0.998
4:88747780:T:G	S745R	0.998

dbSNP variants (sampled 300 via entrez): RS1000003148 (4:88861754 G>A,C,T), RS1000008291 (4:88855584 G>A), RS1000013822 (4:88940426 T>C), RS10000140 (4:89026903 T>C), RS1000024704 (4:89032905 T>C), RS1000027829 (4:88850449 T>C), RS1000064302 (4:88945307 T>C), RS1000069805 (4:88805937 G>C), RS1000079969 (4:88854244 T>C), RS1000080322 (4:88897896 C>T), RS1000094080 (4:88986149 T>G), RS1000094686 (4:88851812 G>A), RS1000096346 (4:89031384 A>C), RS1000098936 (4:88898257 G>A), RS1000108250 (4:89058310 G>A)

Disease associations

OMIM: gene MIM:613299 | disease phenotypes: MIM:606963, MIM:178500, MIM:605543, MIM:613095, MIM:118450, MIM:613443

GenCC curated gene-disease

Mondo (9): chronic obstructive pulmonary disease (MONDO:0005002), combined pulmonary fibrosis-emphysema syndrome (MONDO:0017591), interstitial lung disease 2 (MONDO:0800497), autosomal dominant Parkinson disease 4 (MONDO:0011562), polycystic kidney disease 2 (MONDO:0013131), Alagille syndrome due to a JAG1 point mutation (MONDO:0016862), squamous cell carcinoma (MONDO:0005096), lung adenocarcinoma (MONDO:0005061), neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (MONDO:0013266)

Orphanet (9): Idiopathic pulmonary fibrosis (Orphanet:2032), Combined pulmonary fibrosis-emphysema syndrome (Orphanet:300564), Acute interstitial pneumonia (Orphanet:79126), Hereditary late-onset Parkinson disease (Orphanet:411602), Alagille syndrome due to a JAG1 point mutation (Orphanet:261619), Alagille syndrome (Orphanet:52), 5q14.3 microdeletion syndrome (Orphanet:228384), Brain abnormalities-severe developmental delay-facial dysmorphism-intellectual disability syndrome (Orphanet:664410), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0001063	Acrocyanosis
HP:0002020	Gastroesophageal reflux
HP:0002110	Bronchiectasis
HP:0002206	Pulmonary fibrosis
HP:0002875	Exertional dyspnea
HP:0003546	Exercise intolerance
HP:0006530	Abnormal pulmonary interstitial morphology
HP:0010444	Pulmonic regurgitation
HP:0012378	Fatigue
HP:0012735	Cough
HP:0025175	Honeycomb lung
HP:0025179	Ground-glass opacification
HP:0025390	Reticular pattern on pulmonary HRCT
HP:0030830	Crackles
HP:0031631	Subpleural honeycombing
HP:0031950	Usual interstitial pneumonia
HP:0032341	Reduced forced vital capacity
HP:0033367	Orthodeoxia
HP:0045051	Decreased DLCO
HP:0100759	Clubbing of fingers

GWAS associations

293 associations (top):

Study	Trait	p-value
GCST000514_17	Response to antipsychotic therapy (extrapyramidal side effects)	6.000000e-06
GCST000542_4	Pulmonary function	1.000000e-07
GCST000603_1	Chronic obstructive pulmonary disease	1.000000e-11
GCST001321_1	Chronic obstructive pulmonary disease	2.000000e-09
GCST001784_48	Pulmonary function (smoking interaction)	5.000000e-11
GCST001968_10	Interstitial lung disease	2.000000e-11
GCST002223_31	HDL cholesterol	4.000000e-12
GCST002350_2	Chronic obstructive pulmonary disease (severe)	9.000000e-15
GCST002351_2	Chronic obstructive pulmonary disease (moderate to severe)	1.000000e-14
GCST002624_1	Chronic obstructive pulmonary disease	7.000000e-10
GCST002625_1	Chronic bronchitis and chronic obstructive pulmonary disease	6.000000e-10
GCST002625_7	Chronic bronchitis and chronic obstructive pulmonary disease	2.000000e-10
GCST002782_77	Waist-to-hip ratio adjusted for body mass index	3.000000e-10
GCST002782_78	Waist-to-hip ratio adjusted for body mass index	4.000000e-08
GCST002782_79	Waist-to-hip ratio adjusted for body mass index	3.000000e-11
GCST002782_80	Waist-to-hip ratio adjusted for body mass index	5.000000e-10
GCST002795_1	Chronic obstructive pulmonary disease	1.000000e-10
GCST003262_1003	Post bronchodilator FEV1	3.000000e-07
GCST003262_1004	Post bronchodilator FEV1	3.000000e-07
GCST003262_1006	Post bronchodilator FEV1	3.000000e-07
GCST003262_1007	Post bronchodilator FEV1	3.000000e-07
GCST003262_1008	Post bronchodilator FEV1	3.000000e-07
GCST003262_1011	Post bronchodilator FEV1	1.000000e-06
GCST003262_1022	Post bronchodilator FEV1	5.000000e-07
GCST003262_1023	Post bronchodilator FEV1	5.000000e-07
GCST003262_1024	Post bronchodilator FEV1	6.000000e-07
GCST003262_1042	Post bronchodilator FEV1	9.000000e-08
GCST003262_1049	Post bronchodilator FEV1	2.000000e-06
GCST003262_1050	Post bronchodilator FEV1	5.000000e-06
GCST003262_1051	Post bronchodilator FEV1	3.000000e-07

EFO canonical traits (24, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004713	FEV/FVC ratio
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004314	forced expiratory volume
EFO:0004318	smoking behavior
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0004312	vital capacity
EFO:0009718	peak expiratory flow
EFO:0004531	urate measurement
EFO:0000768	idiopathic pulmonary fibrosis
EFO:0004502	adiponectin measurement
EFO:0004530	triglyceride measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0007800	body fat percentage
EFO:0008039	BMI-adjusted hip circumference
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count
EFO:0009902	handedness
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002294	Carcinoma, Squamous Cell	C04.557.470.200.400; C04.557.470.700.400
D029424	Pulmonary Disease, Chronic Obstructive	C08.381.495.389; C23.550.291.500.875
C565324	Parkinson Disease 4, Autosomal Dominant Lewy Body (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2869950	CHRNB4, FAM13A	3	0.00	1	nicotine

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	3
Aflatoxin B1	decreases expression, decreases methylation	3
cobaltous chloride	increases expression	2
(+)-JQ1 compound	decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Estradiol	decreases expression	2
Oxygen	increases expression	2
Tretinoin	increases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
propionaldehyde	decreases expression	1
bisphenol A	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
nickel chloride	increases expression	1
benzo(e)pyrene	affects methylation	1
resorcinol	increases expression	1
hydroquinone	decreases expression	1
ciglitazone	affects binding, increases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	increases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
vandetanib	increases expression	1
pyrimidifen	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120978	PHASE4	UNKNOWN	Can Advair and Flovent Reduce Systemic Inflammation Related to Chronic Obstructive Pulmonary Disease (COPD)? A Multi-Center Randomized Controlled Trial
NCT00134979	PHASE4	COMPLETED	Formoterol Certihaler, Tiotropium HandiHaler and Tiotropium HandiHaler in Combination With Formoterol Certihaler in Patients With Stable Chronic Obstructive Pulmonary Disease
NCT00158847	PHASE4	TERMINATED	Modification Of Disease Outcome In COPD
NCT00170222	PHASE4	COMPLETED	Placebo Versus Antibiotics in Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)
NCT00175565	PHASE4	COMPLETED	Inhaled Steroid Reduces Systemic Inflammation in COPD
NCT00181207	PHASE4	COMPLETED	Airway Clearance for Prevention of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
NCT00186706	PHASE4	COMPLETED	Selenium Supplementation in Chronic Obstructive Pulmonary Disease (COPD) Patients
NCT00190437	PHASE4	COMPLETED	ANTEAB: a Study of Early Antibiotherapy in the ICU Management of Acute Exacerbations of COPD
NCT00202176	PHASE4	COMPLETED	Effects of Bronchodilators in Mild Chronic Obstructive Pulmonary Disease (COPD)
NCT00202189	PHASE4	COMPLETED	Effects of Inhaled Corticosteroids in Chronic Obstructive Pulmonary Disease (COPD)
NCT00232674	PHASE4	COMPLETED	Efficacy Study of the Effect of Budesonide on Emphysema
NCT00288548	PHASE4	UNKNOWN	Metoprolol and Formoterol in Chronic Obstructive Pulmonary Disease (COPD)
NCT00291408	PHASE4	WITHDRAWN	Effect of Symbicort on HAT and HDAC in Sputum Macrophages of COPD
NCT00291460	PHASE4	UNKNOWN	Inspiratory Muscle Training in Hypercapnic COPD
NCT00292838	PHASE4	COMPLETED	Relative Potency of Inhaled Corticosteroids
NCT00311961	PHASE4	COMPLETED	Intravenous Versus Oral Administration of Prednisolone in Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)
NCT00316992	PHASE4	COMPLETED	Safety of Ramelteon in Subjects With Chronic Obstructive Pulmonary Disease
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00335621	PHASE4	WITHDRAWN	Replacement of Nebulised Ipratropium With Inhaled Tiotropium in Stable Chronic Obstructive Pulmonary Disease (COPD)
NCT00354354	PHASE4	COMPLETED	Bronchodilators and Oxygen Kinetics With Exercise in Chronic Obstructive Pulmonary Disease (COPD) Patients
NCT00379028	PHASE4	COMPLETED	Airway Clearance Study
NCT00405236	PHASE4	COMPLETED	Effect of Tiotropium on Inflammation and Exacerbations in COPD
NCT00412204	PHASE4	COMPLETED	Study to Evaluate the Effects of Tiotropium Bromide on Chronic Obstructive Pulmonary Disease (COPD) During Exercise
NCT00424528	PHASE4	COMPLETED	Efficacy Safety Study of Arformoterol/Tiotropium Combination Versus Either Therapy Alone in Chronic Obstructive Pulmonary Disease (COPD)
NCT00440245	PHASE4	COMPLETED	Bronchoprotection of Salbutamol in Asthma and Chronic Obstructive Pulmonary Disease
NCT00440687	PHASE4	COMPLETED	Withdrawal of Inhaled Corticosteroids in Patients With COPD in Primary Care
NCT00489853	PHASE4	COMPLETED	Evaluation of Efficacy on Exercise Tolerance of Symbicort (Budesonide/Formoterol) Compared to Placebo and Oxis in Patients With Severe COPD
NCT00491803	PHASE4	COMPLETED	Sildenafil Effects on Pulmonary Haemodynamics and Gas Exchange in Chronic Obstructive Pulmonary Disease (COPD)
NCT00495586	PHASE4	COMPLETED	Effectiveness of Antibiotic Therapy for Exacerbations of Chronic Obstructive Pulmonary Disease
NCT00525564	PHASE4	COMPLETED	Effects of Salmeterol on Walking Capacity in Patients With COPD
NCT00532584	PHASE4	WITHDRAWN	Effect of Steroids on Gene Expression in the Healthy Smokers Lungs
NCT00542880	PHASE4	COMPLETED	Evaluation of Onset of Effect in Patients With Severe Chronic Obstructive Pulmonary Disease (COPD) Treated With Symbicort® Compared to Seretide®
NCT00561886	PHASE4	COMPLETED	Change of Inspiratory Peak Flow in COPD
NCT00569270	PHASE4	COMPLETED	Dynamic Hyperinflation and Tiotropium
NCT00571428	PHASE4	COMPLETED	Efficacy Safety Study of Arformoterol QD Dosing Versus BID Dosing in COPD
NCT00578968	PHASE4	COMPLETED	Cardiac Limitations in Chronic Obstructive Pulmonary Disease: Benefits of Bronchodilation
NCT00592033	PHASE4	COMPLETED	Effect of Oxygen in Normoxaemic COPD Patients Who Desaturate During Exercise
NCT00628225	PHASE4	COMPLETED	Smoking Cessation in Patients With COPD (SMOCC) in General Practice
NCT00633776	PHASE4	WITHDRAWN	Perforomist Versus Foradil Evaluated by Inspiratory Capacity and High Resolution Computed Tomography (HRCT)
NCT00639236	PHASE4	COMPLETED	Effectiveness and Safety of Inhaling Hypertonic Saline in Patients With Chronic Obstructive Pulmonary Disease