CHN1

Summary

CHN1 (chimerin 1, HGNC:1943) is a protein-coding gene on chromosome 2q31.1, encoding N-chimaerin (P15882). GTPase-activating protein for p21-rac and a phorbol ester receptor.

This gene encodes GTPase-activating protein for ras-related p21-rac and a phorbol ester receptor. It is predominantly expressed in neurons, and plays an important role in neuronal signal-transduction mechanisms. Mutations in this gene are associated with Duane’s retraction syndrome 2 (DURS2). Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 1123 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Duane retraction syndrome 2 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 154 total — 10 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 63
• MANE Select transcript: NM_001822

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1943
Approved symbol	CHN1
Name	chimerin 1
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Aliases	RhoGAP2, ARHGAP2, n-chimerin
Ensembl gene	ENSG00000128656
Ensembl biotype	protein_coding
OMIM	118423
Entrez	1123

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 22 protein_coding, 12 nonsense_mediated_decay, 6 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000295497, ENST00000409089, ENST00000409156, ENST00000409597, ENST00000409900, ENST00000413882, ENST00000425395, ENST00000443238, ENST00000444394, ENST00000444573, ENST00000451799, ENST00000469597, ENST00000481174, ENST00000485882, ENST00000488080, ENST00000490654, ENST00000491801, ENST00000492964, ENST00000650731, ENST00000650734, ENST00000650770, ENST00000650938, ENST00000651063, ENST00000651246, ENST00000651315, ENST00000651373, ENST00000651501, ENST00000651580, ENST00000651599, ENST00000651717, ENST00000651803, ENST00000651971, ENST00000652036, ENST00000652154, ENST00000652157, ENST00000652208, ENST00000652434, ENST00000652437, ENST00000652674, ENST00000652734, ENST00000652756, ENST00000652768, ENST00000905596, ENST00000934192

RefSeq mRNA: 5 — MANE Select: NM_001822 NM_001025201, NM_001206602, NM_001371513, NM_001371514, NM_001822

CCDS: CCDS46454, CCDS46455, CCDS56147

Canonical transcript exons

ENST00000409900 — 13 exons

Exon	Start	End
ENSE00001924659	174798809	174800287
ENSE00003478963	174877840	174878128
ENSE00003526315	174915058	174915171
ENSE00003560953	174944888	174944943
ENSE00003590474	174824434	174824518
ENSE00003646068	174812309	174812482
ENSE00003650897	174811511	174811588
ENSE00003653818	174952164	174952202
ENSE00003670386	174918534	174918565
ENSE00003671004	174846880	174846957
ENSE00003790921	174808905	174809042
ENSE00003791688	174801707	174801812
ENSE00003850622	175004894	175005381

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 99.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.2230 / max 6932.7957, expressed in 1375 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31915	28.8971	848
31924	5.4695	1048
31914	3.8987	511
31910	1.3387	250
31921	1.2427	512
31913	0.9857	152
31912	0.8256	137
31916	0.7310	160
31917	0.4229	92
31925	0.3610	204

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	99.97	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.96	gold quality
endothelial cell	CL:0000115	99.91	gold quality
primary visual cortex	UBERON:0002436	99.89	gold quality
superior frontal gyrus	UBERON:0002661	99.87	gold quality
orbitofrontal cortex	UBERON:0004167	99.87	gold quality
occipital lobe	UBERON:0002021	99.86	gold quality
frontal pole	UBERON:0002795	99.82	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.82	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.75	gold quality
parietal lobe	UBERON:0001872	99.74	gold quality
postcentral gyrus	UBERON:0002581	99.73	gold quality
CA1 field of hippocampus	UBERON:0003881	99.73	gold quality
entorhinal cortex	UBERON:0002728	99.72	gold quality
prefrontal cortex	UBERON:0000451	99.69	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.66	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.62	gold quality
frontal cortex	UBERON:0001870	99.60	gold quality
frontal lobe	UBERON:0016525	99.60	gold quality
temporal lobe	UBERON:0001871	99.53	gold quality
Ammon’s horn	UBERON:0001954	99.53	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.53	gold quality
right frontal lobe	UBERON:0002810	99.49	gold quality
amygdala	UBERON:0001876	99.41	gold quality
nucleus accumbens	UBERON:0001882	99.38	gold quality
caudate nucleus	UBERON:0001873	99.37	gold quality
putamen	UBERON:0001874	99.35	gold quality
cerebral cortex	UBERON:0000956	99.33	gold quality
pons	UBERON:0000988	99.32	gold quality
cingulate cortex	UBERON:0003027	99.31	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	5903.82
E-HCAD-25	yes	3843.95
E-HCAD-30	yes	3768.00
E-GEOD-180759	yes	2288.96
E-MTAB-7316	yes	15.60
E-ANND-3	yes	6.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYCN, TP63

miRNA regulators (miRDB)

73 targeting CHN1, 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-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-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-3140-3P	99.88	68.47	2069

Literature-anchored findings (GeneRIF, showing 24)

• we show that alpha-chimaerin is a Cdk5p35-binding protein; in transfected HeLa cells, Cdk5p35 and alpha-chimaerin displayed an overlapping distribution pattern (PMID:15013773)
• These two pedigrees double the published pedigrees known to map to the DURS2 locus and can thus contribute toward the search for the DURS2 gene (PMID:17197532)
• DRS (Duane retraction syndrome) linked to the DURS2 locus is associated with bilateral abnormalities of many orbital motor nerves, and structural abnormalities of all EOMs except those innervated by the inferior division of CN3. (PMID:17197533)
• Identify chimaerins as candidates for the downmodulation of Rac1 in T-lymphocytes and, in addition, uncover a novel regulatory mechanism that mediates their activation in T-cells. (PMID:18249095)
• studying families with a variant form of Duane’s retraction syndrome (DURS2-DRS), causative heterozygous missense mutations in CHN1 were identified; these are gain-of-function mutations that increase alpha2-chimaerin RacGAP activity (PMID:18653847)
• analysis of an autoinhibitory mechanism that restricts C1 domain-mediated activation of the Rac-GAP alpha2-chimaerin (PMID:18826946)
• Considerable intrafamilial clinical variability was observed in this Duane syndrome pedigree that carried a alpha2-chimaerin mutation (PMID:19541263)
• study concludes that CHN1 mutations are not a major cause of Duane’s retraction syndrome among individuals with sporadic disease (PMID:20034095)
• We found no evidence for a causative involvement of CHN1 mutations in congenital ocular motor anomalies different from autosomal dominant Duane’s retraction syndrome (PMID:20535495)
• Members of families segregating Duane retraction syndrome (DRS) as an autosomal dominant trait should be screened for mutations in the CHN1 gene, enhancing genetic counseling and permitting earlier diagnosis. (PMID:21555619)
• Analysis of the current pedigree expands the phenotypic spectrum of hyperactivating CHN1 mutations to include vertical strabismus and supraduction deficits in the absence of Duane retraction syndrome. (PMID:21715346)
• The patients most similar belong to families with a small or absent cranial nerve VI and septo-optic hypoplasia who carry CHN1 mutations (PMID:25331612)
• reduced alpha1-chimaerin expression in the brain of Alzheimer’s disease cases, suggesting a role in the upregulation of Rac1 activity during the disease process. (PMID:25676811)
• CHN1 and TNFAIP3 are candidate biomarkers for esophageal squamous cell carcinomas (PMID:27072986)
• this study shows that serum chemerin is an independent risk factor of prognosis of non-small cell lung cancer patients (PMID:28160556)
• These findings reveal a role for ephrin bidirectional signaling upstream of mutant alpha2-chimaerin in Duane retraction syndrome, which may contribute to the selective vulnerability of abducens motor neurons in this disorder (PMID:28346224)
• CHN1 mutations were identified in 2 bilateral cases and in 1 parent of 1 affected case. One mutation is novel and occurred with additional vertical gaze abnormalities. (PMID:29031989)
• The results suggest that chemerin plays an important role in inhibiting the cell proliferation of hepatocellular carcinomas by interfering with cellular iron homeostasis in this type of tumors. (PMID:29872820)
• Identification of a novel CHN1 p.(Phe213Val) variant in a large Han Chinese family with congenital Duane retraction syndrome. (PMID:33004823)
• Upregulation of miR-205 induces CHN1 expression, which is associated with the aggressive behaviour of cervical cancer cells and correlated with lymph node metastasis. (PMID:33109127)
• CHN1 and duane retraction syndrome: Expanding the phenotype to cranial nerves development disease. (PMID:33667650)
• Bioinformatics-based analysis of the association between the A1-chimaerin (CHN1) gene and gastric cancer. (PMID:34152250)
• CHN1 promotes epithelial-mesenchymal transition via the Akt/GSK-3beta/Snail pathway in cervical carcinoma. (PMID:34238315)
• Special clinical features with a novel mutation site of CHN1 gene in a Chinese family with Duane retraction syndrome. (PMID:38509018)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	chn1	ENSDARG00000101735
mus_musculus	Chn1	ENSMUSG00000056486
rattus_norvegicus	Chn1	ENSRNOG00000017939
rattus_norvegicus	AABR07032856.1	ENSRNOG00000038211
drosophila_melanogaster	RhoGAP5A	FBGN0029778
caenorhabditis_elegans		WBGENE00015267

Paralogs (4): SYDE2 (ENSG00000097096), SYDE1 (ENSG00000105137), CHN2 (ENSG00000106069), ARHGAP35 (ENSG00000160007)

Protein

Protein identifiers

N-chimaerin — P15882 (reviewed: P15882)

Alternative names: A-chimaerin, Alpha-chimerin, N-chimerin, Rho GTPase-activating protein 2

All UniProt accessions (25): P15882, A0A494BZY1, A0A494C047, A0A494C072, A0A494C0C9, A0A494C0I4, A0A494C0I5, A0A494C0L5, A0A494C0R6, A0A494C0V1, A0A494C158, A0A494C1D3, A0A494C1H3, A0A494C1M7, A0A494C1P5, A0A494C1Q9, A0A494C1R0, B8ZZ96, C9J1N1, C9J3G1, C9J3V9, C9JR98, F8W6K2, F8WAY4, F8WCQ9

UniProt curated annotations — full annotation on UniProt →

Function. GTPase-activating protein for p21-rac and a phorbol ester receptor. Involved in the assembly of neuronal locomotor circuits as a direct effector of EPHA4 in axon guidance.

Subunit / interactions. Interacts with EPHA4; effector of EPHA4 in axon guidance linking EPHA4 activation to RAC1 regulation.

Tissue specificity. In neurons in brain regions that are involved in learning and memory processes.

Post-translational modifications. Phosphorylated. Phosphorylation is EPHA4 kinase activity-dependent.

Disease relevance. Duane retraction syndrome 2 (DURS2) [MIM:604356] A form of Duane retraction syndrome, a congenital eye movement disorder characterized by a failure of cranial nerve VI (the abducens nerve) to develop normally, resulting in restriction or absence of abduction, adduction or both, narrowing of the palpebral fissure, and retraction of the globe on attempted adduction. Undiagnosed in children, it can lead to amblyopia, a permanent uncorrectable loss of vision. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
P15882-1	Alpha-2	yes
P15882-2	Alpha-1
P15882-3	3

RefSeq proteins (5): NP_001020372, NP_001193531, NP_001358442, NP_001358443, NP_001813* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR000980	SH2	Domain
IPR002219	PKC_DAG/PE	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR017356	CHN1/CHN2	Family
IPR020454	DAG/PE-bd	Domain
IPR035840	Chimaerin_SH2	Domain
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR037860	RhoGAP_chimaerin	Domain
IPR046349	C1-like_sf	Homologous_superfamily
IPR051854	Rho-type_GAP	Family

Pfam: PF00017, PF00130, PF00620

UniProt features (52 total): helix 19, strand 9, sequence variant 7, turn 6, modified residue 3, splice variant 2, domain 2, initiator methionine 1, chain 1, zinc finger region 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2OSA	X-RAY DIFFRACTION	1.8
3CXL	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15882-F1	86.41	0.77

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): 304 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Post-translational modifications (3): 2, 192, 340

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle

MSigDB gene sets: 337 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, JOHANSSON_GLIOMAGENESIS_BY_PDGFB_DN, GOBP_NEUROGENESIS, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_MOTOR_NEURON_AXON_GUIDANCE, JOHANSSON_BRAIN_CANCER_EARLY_VS_LATE_DN, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, FREAC3_01, LU_TUMOR_VASCULATURE_UP, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM5

GO Biological Process (7): motor neuron axon guidance (GO:0008045), ephrin receptor signaling pathway (GO:0048013), regulation of axonogenesis (GO:0050770), regulation of small GTPase mediated signal transduction (GO:0051056), signal transduction (GO:0007165), nervous system development (GO:0007399), positive regulation of GTPase activity (GO:0043547)

GO Molecular Function (5): GTPase activator activity (GO:0005096), zinc ion binding (GO:0008270), ephrin receptor binding (GO:0046875), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (2): cytosol (GO:0005829), membrane (GO:0016020)

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
GTPase activity	2
cellular anatomical structure	2
axon guidance	1
cell surface receptor protein tyrosine kinase signaling pathway	1
axonogenesis	1
regulation of neuron projection development	1
regulation of anatomical structure morphogenesis	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
system development	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
enzyme activator activity	1
GTPase regulator activity	1
transition metal ion binding	1
signaling receptor binding	1
binding	1
cation binding	1
cytoplasm	1

Protein interactions and networks

STRING

1004 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHN1	HOXA1	P49639	847
CHN1	ROBO3	Q96MS0	825
CHN1	SALL4	Q9UJQ4	823
CHN1	RASA1	P20936	740
CHN1	EPHA4	P54764	740
CHN1	HOXB1	P14653	671
CHN1	CDC42	P21181	671
CHN1	DGKG	P49619	670
CHN1	HOXD1	Q9GZZ0	648
CHN1	AKT1	P31749	621
CHN1	KIF21A	Q7Z4S6	546
CHN1	TMED10	P49755	525
CHN1	EYA1	Q99502	497
CHN1	SEMA3F	Q13275	484
CHN1	KLC1	Q07866	484

IntAct

46 interactions, top by confidence:

A	B	Type	Score
NCK2	CHN1	psi-mi:“MI:0915”(physical association)	0.890
CHN1	NCK2	psi-mi:“MI:0915”(physical association)	0.890
CHN1	HEMK1	psi-mi:“MI:0915”(physical association)	0.780
HEMK1	CHN1	psi-mi:“MI:0915”(physical association)	0.780
CHN1	MAPK1	psi-mi:“MI:0915”(physical association)	0.560
CHN1	ANKK1	psi-mi:“MI:0915”(physical association)	0.560
CDK5R1	CHN1	psi-mi:“MI:0915”(physical association)	0.540
CHN1	CDK5R1	psi-mi:“MI:0403”(colocalization)	0.540
NCK1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
ERBB2	CHN1	psi-mi:“MI:0407”(direct interaction)	0.440
CHN1	ALDH1A1	psi-mi:“MI:0915”(physical association)	0.400
CHN1	CHN2	psi-mi:“MI:0915”(physical association)	0.400
CHN1	ADORA2A	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (41): NCK2 (Two-hybrid), HEMK1 (Two-hybrid), CHN1 (Synthetic Lethality), NCK2 (Two-hybrid), NCK2 (Two-hybrid), CHN2 (Affinity Capture-MS), CHN1 (Affinity Capture-RNA), CHN1 (Affinity Capture-MS), CHN1 (Synthetic Lethality), GTF3C1 (Two-hybrid), RPS3A (Two-hybrid), CHN1 (Two-hybrid), CHN1 (Two-hybrid), CHN1 (Two-hybrid), ANKK1 (Two-hybrid)

ESM2 similar proteins: A0A7U2QYM2, A0FKG7, A1Z6E0, A2X0Q3, A8QGZ7, A8XT88, B0X9V1, B3MDR0, B3NRP1, B4F739, B4GBN7, B4HQ29, B4J6Q0, B4KNC5, B4LMQ3, B4MR59, B4P4K8, B4QE02, D4ABP9, P0C2W1, P0CH38, P15882, P18163, P29074, P37287, P52757, Q16XV7, Q18223, Q1JPS1, Q27601, Q290L5, Q2RAX3, Q3SX24, Q6NZ03, Q6YXZ7, Q7QGL9, Q7ZXY1, Q8K3B1, Q91V57, Q9JID6

Diamond homologs: A0A0G2JTR4, A1A4S6, A2AB59, A2RUV4, A4IF90, A4II46, A6QNS3, A6X8Z5, A7KAX9, A7YY57, A8WRJ2, D3ZFJ3, E7EZG2, E7F3F0, F1LXF1, O14559, O94466, P11274, P15882, P30337, P34288, P38339, P46941, P52757, P55194, P81128, P97393, Q03070, Q08DP6, Q10164, Q12979, Q13017, Q15311, Q17QN0, Q20498, Q2M1Z3, Q3TBD2, Q3UIA2, Q52LW3, Q53QZ3

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CHN1	up-regulates	CDK5R1	binding
CHN1	“down-regulates activity”	RAC1	“gtpase-activating protein”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 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
Signaling by Receptor Tyrosine Kinases	5	19.9×	6e-04
Axon guidance	5	17.4×	6e-04
Nervous system development	5	16.5×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	3
Uncertain significance	95
Likely benign	10
Benign	8

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
17550	NM_001822.7(CHN1):c.60A>T (p.Leu20Phe)	Pathogenic
17551	NM_001822.7(CHN1):c.378T>G (p.Ile126Met)	Pathogenic
17552	NM_001822.7(CHN1):c.427T>C (p.Tyr143His)	Pathogenic
17553	NM_001822.7(CHN1):c.668C>T (p.Ala223Val)	Pathogenic
17554	NM_001822.7(CHN1):c.682G>A (p.Gly228Ser)	Pathogenic
17555	NM_001822.7(CHN1):c.755C>A (p.Pro252Gln)	Pathogenic
17556	NM_001822.7(CHN1):c.937G>A (p.Glu313Lys)	Pathogenic
29623	NM_001822.7(CHN1):c.422C>T (p.Pro141Leu)	Pathogenic
559835	NM_001822.7(CHN1):c.661T>C (p.Tyr221His)	Pathogenic
974781	NM_001822.7(CHN1):c.1106T>G (p.Ile369Ser)	Pathogenic
1708248	NM_001822.7(CHN1):c.643G>A (p.Gly215Arg)	Likely pathogenic
4072045	NM_001822.7(CHN1):c.428A>G (p.Tyr143Cys)	Likely pathogenic
598971	NM_001822.7(CHN1):c.667G>A (p.Ala223Thr)	Likely pathogenic

SpliceAI

3983 predictions. Top by Δscore:

Variant	Effect	Δscore
2:174800286:CT:C	acceptor_gain	1.0000
2:174800288:C:CC	acceptor_gain	1.0000
2:174801834:C:CT	acceptor_gain	1.0000
2:174801835:A:T	acceptor_gain	1.0000
2:174809052:A:AC	acceptor_gain	1.0000
2:174809052:A:C	acceptor_gain	1.0000
2:174809055:T:C	acceptor_gain	1.0000
2:174809055:T:TC	acceptor_gain	1.0000
2:174811506:CATA:C	donor_loss	1.0000
2:174811507:ATACC:A	donor_loss	1.0000
2:174811508:TACCT:T	donor_loss	1.0000
2:174811509:A:AC	donor_gain	1.0000
2:174811510:C:CC	donor_gain	1.0000
2:174811510:CCT:C	donor_gain	1.0000
2:174811584:AAGAC:A	acceptor_gain	1.0000
2:174811585:AGAC:A	acceptor_gain	1.0000
2:174811586:GAC:G	acceptor_gain	1.0000
2:174811589:C:CA	acceptor_loss	1.0000
2:174811589:C:CC	acceptor_gain	1.0000
2:174811590:T:C	acceptor_loss	1.0000
2:174812303:GCTCA:G	donor_loss	1.0000
2:174812304:CTCA:C	donor_loss	1.0000
2:174812305:TCA:T	donor_loss	1.0000
2:174812307:A:C	donor_loss	1.0000
2:174812342:C:CT	donor_gain	1.0000
2:174812343:C:CT	donor_gain	1.0000
2:174812479:CAAT:C	acceptor_gain	1.0000
2:174812483:C:CC	acceptor_gain	1.0000
2:174875780:TTAC:T	donor_loss	1.0000
2:174875782:A:AC	donor_gain	1.0000

AlphaMissense

3038 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:174800219:A:G	L426P	1.000
2:174800228:C:T	G423E	1.000
2:174800229:C:G	G423R	1.000
2:174800229:C:T	G423R	1.000
2:174800234:A:T	V421D	1.000
2:174800240:C:T	G419E	1.000
2:174800243:A:G	L418P	1.000
2:174800258:A:G	M413T	1.000
2:174801713:A:G	L401P	1.000
2:174801725:A:G	L397P	1.000
2:174801734:A:G	L394P	1.000
2:174808958:A:C	L350W	1.000
2:174808975:T:A	K344N	1.000
2:174808975:T:G	K344N	1.000
2:174808977:T:C	K344E	1.000
2:174808979:A:G	L343P	1.000
2:174811555:C:T	G307E	1.000
2:174811556:C:G	G307R	1.000
2:174811556:C:T	G307R	1.000
2:174811564:C:G	R304P	1.000
2:174811565:G:C	R304G	1.000
2:174811573:C:T	G301E	1.000
2:174811574:C:G	G301R	1.000
2:174811574:C:T	G301R	1.000
2:174812331:G:C	C288W	1.000
2:174812333:A:G	C288R	1.000
2:174812430:A:C	C255W	1.000
2:174812431:C:G	C255S	1.000
2:174812431:C:T	C255Y	1.000
2:174812432:A:G	C255R	1.000

dbSNP variants (sampled 300 via entrez): RS1000008152 (2:174847182 A>G), RS1000012075 (2:174802306 ACT>A), RS1000025600 (2:174956615 T>C), RS1000050029 (2:174942281 G>C), RS1000084685 (2:174848756 T>G), RS1000097968 (2:174915503 G>T), RS1000107910 (2:174840249 A>T), RS1000124489 (2:174919180 A>G), RS1000133260 (2:175005559 G>T), RS1000138239 (2:174809917 A>C), RS1000141495 (2:174983796 C>A), RS1000167993 (2:174875157 G>A,T), RS1000223209 (2:174867937 A>G), RS1000225958 (2:174966156 TG>T,TGG), RS1000289355 (2:174899039 C>G)

Disease associations

OMIM: gene MIM:118423 | disease phenotypes: MIM:157900, MIM:604356, MIM:126800, MIM:616331

GenCC curated gene-disease

Disease	Classification	Inheritance
Duane retraction syndrome 2	Strong	Autosomal dominant
Duane retraction syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Duane retraction syndrome 2	Moderate	AD

Mondo (5): Mobius syndrome (MONDO:0008006), Duane retraction syndrome 2 (MONDO:0011444), Duane syndrome type 1 (MONDO:0024265), autosomal dominant Robinow syndrome 2 (MONDO:0014591), Duane retraction syndrome (MONDO:0007473)

Orphanet (4): Moebius syndrome (Orphanet:570), Duane retraction syndrome (Orphanet:233), Autosomal dominant Robinow syndrome (Orphanet:3107), Robinow syndrome (Orphanet:97360)

HPO phenotypes

63 total (30 of 63 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000086	Ectopic kidney
HP:0000175	Cleft palate
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000324	Facial asymmetry
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000384	Preauricular skin tag
HP:0000402	Stenosis of the external auditory canal
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000496	Abnormality of eye movement
HP:0000508	Ptosis
HP:0000526	Aniridia
HP:0000542	Impaired ocular adduction
HP:0000567	Chorioretinal coloboma
HP:0000581	Blepharophimosis
HP:0000612	Iris coloboma
HP:0000615	Abnormal pupil morphology
HP:0000634	Impaired ocular abduction
HP:0000639	Nystagmus
HP:0000643	Blepharospasm

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003262_349	Post bronchodilator FEV1	2.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D004370	Duane Retraction Syndrome	C10.292.562.700.375.500; C11.270.235; C11.590.436.400.500; C16.320.290.235
D020331	Mobius Syndrome	C07.465.299.825; C10.292.319.825; C10.292.562.700.375.750; C11.590.436.400.750; C16.131.077.578; C16.614.595

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance	3
Cyclosporine	decreases expression, increases expression	3
bisphenol A	increases methylation, decreases expression, affects cotreatment	2
Air Pollutants	increases abundance, increases oxidation, decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
GSK-J4	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
deoxynivalenol	decreases expression	1
trichostatin A	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
sulforaphane	increases expression	1
cobaltous chloride	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
CGP 52608	affects binding, increases reaction	1
deguelin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
pyrachlostrobin	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
NSC 689534	affects binding, decreases expression	1
Temozolomide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Arsenic	increases abundance, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	decreases expression, affects cotreatment	1
Copper	affects binding, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03059420	Not specified	RECRUITING	Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies