AFG2A

Summary

AFG2A (AAA ATPase AFG2A, HGNC:18119) is a protein-coding gene on chromosome 4q28.1, encoding ATPase family gene 2 protein homolog A (Q8NB90). ATP-dependent chaperone part of the 55LCC heterohexameric ATPase complex which is chromatin-associated and promotes replisome proteostasis to maintain replication fork progression and genome stability. It is a common-essential gene (DepMap: required in 90.6% of cancer cell lines).

This gene encodes a member of the ATPase associated with diverse activities family, whose members are defined by a highly conserved ATPase domain. Members of this family participate in diverse cellular processes that include membrane fusion, DNA replication, microtubule severing, and protein degradation. The protein encoded by this gene has a putative mitochondrial targeting sequence and has been proposed to function in maintenance of mitochondrial function and integrity during mouse spermatogenesis. Allelic variants in this gene have been associated with epilepsy, hearing loss, and cognitive disability syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 166378 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 25
• Clinical variants (ClinVar): 948 total — 67 pathogenic, 37 likely-pathogenic
• Phenotypes (HPO): 66
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 90.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_145207

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18119
Approved symbol	AFG2A
Name	AAA ATPase AFG2A
Location	4q28.1
Locus type	gene with protein product
Status	Approved
Aliases	SPAF, AFG2
Ensembl gene	ENSG00000145375
Ensembl biotype	protein_coding
OMIM	613940
Entrez	166378

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000274008, ENST00000422835, ENST00000674886, ENST00000675392, ENST00000675612, ENST00000905944, ENST00000905945, ENST00000905946, ENST00000905947, ENST00000971802

RefSeq mRNA: 3 — MANE Select: NM_145207 NM_001317799, NM_001345856, NM_145207

CCDS: CCDS3730

Canonical transcript exons

ENST00000274008 — 16 exons

Exon	Start	End
ENSE00001231994	123256016	123256180
ENSE00001232063	123313888	123319433
ENSE00001895453	122923078	122923305
ENSE00003482337	122936100	122936156
ENSE00003495729	122935714	122935843
ENSE00003517800	123090579	123090705
ENSE00003546039	122934097	122934738
ENSE00003568683	122947233	122947488
ENSE00003587671	123057209	123057288
ENSE00003602798	122933439	122933497
ENSE00003604170	123056387	123056440
ENSE00003609672	122929040	122929197
ENSE00003612001	123028186	123028395
ENSE00003613059	122927634	122927758
ENSE00003666035	122979232	122979386
ENSE00003668882	122938126	122938249

Expression profiles

Bgee: expression breadth ubiquitous, 211 present calls, max score 90.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.0178 / max 273.2724, expressed in 1769 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49558	15.0798	1765
49559	0.9380	527

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	90.55	gold quality
calcaneal tendon	UBERON:0003701	87.35	gold quality
tendon	UBERON:0000043	87.26	gold quality
palpebral conjunctiva	UBERON:0001812	84.62	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.16	gold quality
eye	UBERON:0000970	81.27	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.07	gold quality
bone marrow cell	CL:0002092	80.93	gold quality
ventricular zone	UBERON:0003053	79.24	gold quality
medial globus pallidus	UBERON:0002477	78.31	gold quality
adrenal tissue	UBERON:0018303	77.36	gold quality
oviduct epithelium	UBERON:0004804	76.46	gold quality
sural nerve	UBERON:0015488	76.30	gold quality
colonic epithelium	UBERON:0000397	76.05	gold quality
ganglionic eminence	UBERON:0004023	74.44	gold quality
stromal cell of endometrium	CL:0002255	73.77	gold quality
secondary oocyte	CL:0000655	72.12	gold quality
islet of Langerhans	UBERON:0000006	71.41	gold quality
pigmented layer of retina	UBERON:0001782	71.17	gold quality
tibia	UBERON:0000979	70.95	gold quality
kidney epithelium	UBERON:0004819	70.65	gold quality
cortical plate	UBERON:0005343	70.50	gold quality
globus pallidus	UBERON:0001875	70.42	gold quality
tonsil	UBERON:0002372	69.39	gold quality
smooth muscle tissue	UBERON:0001135	68.96	gold quality
left ventricle myocardium	UBERON:0006566	68.74	gold quality
visceral pleura	UBERON:0002401	68.05	gold quality
cardiac muscle of right atrium	UBERON:0003379	67.90	gold quality
ectocervix	UBERON:0012249	67.78	gold quality
lower lobe of lung	UBERON:0008949	67.59	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.21
E-MTAB-6386	no	339.23

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

167 targeting AFG2A, 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-3613-3P	100.00	76.36	7965
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-495-3P	99.96	72.81	4197

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 90.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 7)

• SPATA5 locus is a new susceptibility locus for Alopecia areata (AA). (PMID:22027810)
• Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss. (PMID:26299366)
• Clinical delineation of the SPATA5-related encephalopathy should improve diagnosis, facilitating further clinical and molecular investigation (PMID:27246907)
• SPATA5 defects may account for a fraction of isolated sensorineural hearing impairment cases. (PMID:28293831)
• Increased DNA methylation in the spermatogenesis-associated (SPATA) genes correlates with infertility. (PMID:31838782)
• A Genome-wide Association Study for Concussion Risk. (PMID:33017352)
• Labeling of heterochronic ribosomes reveals C1ORF109 and SPATA5 control a late step in human ribosome assembly. (PMID:35354024)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Afg2a	ENSMUSG00000027722
rattus_norvegicus	Afg2a	ENSRNOG00000017462
drosophila_melanogaster	CG5776	FBGN0032450
caenorhabditis_elegans	cdc-48.3	WBGENE00010562

Paralogs (5): PEX6 (ENSG00000124587), PEX1 (ENSG00000127980), NVL (ENSG00000143748), VCP (ENSG00000165280), AFG2B (ENSG00000171763)

Protein

Protein identifiers

ATPase family gene 2 protein homolog A — Q8NB90 (reviewed: Q8NB90)

Alternative names: AFG2 AAA ATPase homolog A, Ribosome biogenesis protein SPATA5, Spermatogenesis-associated factor protein, Spermatogenesis-associated protein 5

All UniProt accessions (2): A0A6Q8PGU6, Q8NB90

UniProt curated annotations — full annotation on UniProt →

Function. ATP-dependent chaperone part of the 55LCC heterohexameric ATPase complex which is chromatin-associated and promotes replisome proteostasis to maintain replication fork progression and genome stability. Required for replication fork progression, sister chromatid cohesion, and chromosome stability. The ATPase activity is specifically enhanced by replication fork DNA and is coupled to cysteine protease-dependent cleavage of replisome substrates in response to replication fork damage. Uses ATPase activity to process replisome substrates in S-phase, facilitating their proteolytic turnover from chromatin to ensure DNA replication and mitotic fidelity. Plays an essential role in the cytoplasmic maturation steps of pre-60S ribosomal particles by promoting the release of shuttling protein RSL24D1/RLP24 from the pre-ribosomal particles. May be involved in morphological and functional mitochondrial transformations during spermatogenesis.

Subunit / interactions. Part of the 55LCC heterohexameric ATPase complex composed at least of AIRIM, AFG2A, AFG2B and CINP. Associates with pre-60S ribosomal particles.

Subcellular location. Cytoplasm. Mitochondrion. Cytoskeleton. Spindle.

Disease relevance. Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB) [MIM:616577] An autosomal recessive disorder characterized by intellectual disability, intractable epilepsy, microcephaly, abnormal muscle tone, and sensorineural hearing loss. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. AFG2A alone display limited ATPase activity and is not regulated by RNA or DNA binding. In the context of 55LCC heterohexameric ATPase complex, the ATPase activity increases and is stimulated by DNA binding and inhibited in presence of RNA.

Domain organisation. The first ATP-binding region binds ATP with low affinity whereas the second ATP-binding region binds ATP with high affinity.

Similarity. Belongs to the AAA ATPase family. AFG2 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NB90-1	1	yes
Q8NB90-2	2
Q8NB90-3	3

RefSeq proteins (3): NP_001304728, NP_001332785, NP_660208* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR003960	ATPase_AAA_CS	Conserved_site
IPR009010	Asp_de-COase-like_dom_sf	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR041569	AAA_lid_3	Domain
IPR050168	AAA_ATPase_domain	Family

Pfam: PF00004, PF17862

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (40 total): sequence variant 14, sequence conflict 9, splice variant 4, modified residue 3, region of interest 2, mutagenesis site 2, compositionally biased region 2, binding site 2, chain 1, cross-link 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9LGO	ELECTRON MICROSCOPY	3.51
8RHN	ELECTRON MICROSCOPY	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NB90-F1	73.21	0.17

Functional residue map

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

Ligand- & substrate-binding residues (2): 394–401; 668–675

Post-translational modifications (4): 859, 272, 274, 279

Mutagenesis-validated functional residues (2):

Position	Phenotype
185	no effect on protein stability. no effect on interaction with afg2b.
323	reduces protein stability.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 254 (showing top): GOBP_RIBOSOME_BIOGENESIS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_MALE_GAMETE_GENERATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, KOYAMA_SEMA3B_TARGETS_UP, GARCIA_TARGETS_OF_FLI1_AND_DAX1_DN, GOBP_HEAD_DEVELOPMENT, FISCHER_DREAM_TARGETS, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS, GOBP_RIBOSOMAL_LARGE_SUBUNIT_BIOGENESIS, GOBP_DNA_REPLICATION, GOCC_SPINDLE, GOCC_ATPASE_COMPLEX, GOBP_DNA_METABOLIC_PROCESS

GO Biological Process (5): spermatogenesis (GO:0007283), brain development (GO:0007420), cell differentiation (GO:0030154), ribosomal large subunit biogenesis (GO:0042273), ribosome biogenesis (GO:0042254)

GO Molecular Function (7): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), preribosome binding (GO:1990275), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787), protein-containing complex binding (GO:0044877)

GO Cellular Component (4): cytoplasm (GO:0005737), spindle (GO:0005819), cytosol (GO:0005829), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ribonucleoprotein complex biogenesis	2
binding	2
cellular anatomical structure	2
intracellular membraneless organelle	2
developmental process involved in reproduction	1
male gamete generation	1
central nervous system development	1
animal organ development	1
head development	1
cellular developmental process	1
ribosome biogenesis	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
ribonucleoprotein complex binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
intracellular anatomical structure	1
microtubule cytoskeleton	1
cytoplasm	1

Protein interactions and networks

STRING

3168 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AFG2A	AFG1L	Q8WV93	984
AFG2A	UBE4B	O95155	893
AFG2A	RPAP3	Q9H6T3	663
AFG2A	UBE4A	Q14139	634
AFG2A	NUDT6	P53370	579
AFG2A	AFG2B	Q9BVQ7	471
AFG2A	H1-8	Q8IZA3	441
AFG2A	SPRED3	Q2MJR0	426
AFG2A	RSL24D1	Q9UHA3	412
AFG2A	YLPM1	P49750	411
AFG2A	KCNQ2	O43526	403
AFG2A	SPRY3	O43610	394
AFG2A	ANKRD50	Q9ULJ7	390
AFG2A	SPATA4	Q8NEY3	380
AFG2A	SPRED2	Q7Z698	379

IntAct

102 interactions, top by confidence:

A	B	Type	Score
POLD3	POLD1	psi-mi:“MI:0914”(association)	0.900
CINP	AFG2A	psi-mi:“MI:0914”(association)	0.830
AFG2A	AFG2B	psi-mi:“MI:0915”(physical association)	0.800
AFG2A	AFG2B	psi-mi:“MI:0407”(direct interaction)	0.800
AFG2B	AFG2A	psi-mi:“MI:0914”(association)	0.800
AFG2A	AFG2B	psi-mi:“MI:0914”(association)	0.800
PSMC5	PSMD11	psi-mi:“MI:0914”(association)	0.730
AIRIM	AFG2A	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PSMC4	PSMD11	psi-mi:“MI:0914”(association)	0.670
B3GNT3	PGRMC1	psi-mi:“MI:0914”(association)	0.670
PSMD14	PSMD11	psi-mi:“MI:0914”(association)	0.650
CINP	KIF7	psi-mi:“MI:0914”(association)	0.640
FAM174A	GAK	psi-mi:“MI:0914”(association)	0.640
NSA2	GNL2	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
CINP	CHMP2A	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
CCT8L2	ACSL4	psi-mi:“MI:0914”(association)	0.530
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530

BioGRID (124): SPATA5 (Affinity Capture-MS), SPATA5 (Affinity Capture-MS), SPATA5 (Affinity Capture-MS), SPATA5 (Affinity Capture-MS), SPATA5 (Proximity Label-MS), SPATA5 (Affinity Capture-MS), SPATA5 (Affinity Capture-MS), SPATA5 (Affinity Capture-MS), SPATA5 (Affinity Capture-MS), SPATA5 (Affinity Capture-MS), SPATA5 (Affinity Capture-MS), SPATA5 (Affinity Capture-MS), SPATA5 (Affinity Capture-MS), SPATA5L1 (Affinity Capture-MS), CINP (Affinity Capture-MS)

ESM2 similar proteins: A0A061IR73, A0A0U1RPR8, A0A7N9VSG0, A7YSY2, D3ZX08, D4A2B7, O15381, O19114, O43542, O43824, O88202, P32794, P40694, P51839, P51840, P52333, P52785, P54777, P55205, Q02846, Q08DH8, Q0VA52, Q13608, Q14CH7, Q1HG60, Q2NKY8, Q3U6U5, Q3UMC0, Q3ZBE0, Q5BJS0, Q5E9L5, Q5JTZ9, Q5PQY6, Q5R607, Q5RCH4, Q6NZB1, Q6ZSI9, Q7L2E3, Q80SX8, Q8NB90

Diamond homologs: A0A061IR73, A0A7N9VSG0, A4G0S4, A6UQT3, A6VHR1, A7YSY2, A9A916, C4QXI8, C4R6C2, D1CDT8, D4A2B7, G1X4S3, G1X7C7, G3GXG9, O05209, O13764, O14325, O15381, O18413, O26824, O28303, O28972, O43933, O60058, O74941, P03974, P23787, P24004, P25694, P32794, P33289, P33760, P34124, P36966, P41836, P46462, P46463, P46468, P54609, P54774

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SPATA5	“form complex”	“SPATA5-SPATA5L1 ATPase complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 108 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
AUF1 (hnRNP D0) binds and destabilizes mRNA	5	18.2×	1e-03
Defective CFTR causes cystic fibrosis	5	16.1×	2e-03
Proteasome assembly	5	15.0×	2e-03
Regulation of RUNX2 expression and activity	5	13.3×	3e-03
The role of GTSE1 in G2/M progression after G2 checkpoint	5	11.8×	3e-03
Hedgehog ‘on’ state	5	11.7×	3e-03
Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide	7	11.0×	7e-04
CLEC7A (Dectin-1) signaling	5	10.5×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	67
Likely pathogenic	37
Uncertain significance	401
Likely benign	333
Benign	49

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1031192	NM_145207.3(AFG2A):c.2306del (p.Leu769fs)	Pathogenic
1069922	NM_145207.3(AFG2A):c.85G>T (p.Glu29Ter)	Pathogenic
1075382	NC_000004.11:g.(?124011714)(124011880_?)del	Pathogenic
1075383	NC_000004.11:g.(?123977532)(123978453_?)del	Pathogenic
1341484	NM_145207.3(AFG2A):c.2131_2134del (p.Glu711fs)	Pathogenic
1398827	NC_000004.11:g.(?123859261)(123859424_?)del	Pathogenic
1438535	NM_145207.3(AFG2A):c.2084del (p.Pro695fs)	Pathogenic
1443130	NM_145207.3(AFG2A):c.1073T>G (p.Leu358Ter)	Pathogenic
1452126	NM_145207.3(AFG2A):c.110C>G (p.Ser37Ter)	Pathogenic
1452600	NM_145207.3(AFG2A):c.1714+1G>C	Pathogenic
1453890	NM_145207.3(AFG2A):c.2362_2371del (p.Ile788fs)	Pathogenic
1457120	NM_145207.3(AFG2A):c.595_596del (p.Asp199fs)	Pathogenic
1460171	NC_000004.11:g.(?123900367)(124011880_?)del	Pathogenic
1527122	GRCh37/hg19 4q28.1(chr4:123952079-124000607)x1	Pathogenic
1679513	NM_145207.3(AFG2A):c.2004del (p.Pro669fs)	Pathogenic
1695107	NM_145207.3(AFG2A):c.1607del (p.Leu536fs)	Pathogenic
1698549	NC_000004.11:g.(123949551_123977541)_(123978444_124011733)del	Pathogenic
1964318	NM_145207.3(AFG2A):c.853G>T (p.Glu285Ter)	Pathogenic
203527	NM_145207.3(AFG2A):c.1343C>T (p.Ser448Leu)	Pathogenic
203529	NM_145207.3(AFG2A):c.1574_1578del (p.Asn525fs)	Pathogenic
203534	NM_145207.3(AFG2A):c.251G>A (p.Arg84Gln)	Pathogenic
203536	NM_145207.3(AFG2A):c.298G>A (p.Ala100Thr)	Pathogenic
204306	NM_145207.3(AFG2A):c.556C>T (p.Arg186Ter)	Pathogenic
2056929	NM_145207.3(AFG2A):c.10A>T (p.Lys4Ter)	Pathogenic
207803	NM_145207.3(AFG2A):c.1714+1G>A	Pathogenic
207827	NM_145207.3(AFG2A):c.1677C>A (p.Tyr559Ter)	Pathogenic
2100148	NM_145207.3(AFG2A):c.1254_1257del (p.Ile418fs)	Pathogenic
2111243	NM_145207.3(AFG2A):c.845_846del (p.Met282fs)	Pathogenic
2114198	NM_145207.3(AFG2A):c.1983dup (p.Lys662Ter)	Pathogenic
2125633	NM_145207.3(AFG2A):c.1761del (p.Asp588fs)	Pathogenic

SpliceAI

4615 predictions. Top by Δscore:

Variant	Effect	Δscore
4:122923304:GG:G	donor_gain	1.0000
4:122923305:GG:G	donor_gain	1.0000
4:122927632:A:AG	acceptor_gain	1.0000
4:122927633:G:GG	acceptor_gain	1.0000
4:122927633:GT:G	acceptor_gain	1.0000
4:122927633:GTA:G	acceptor_gain	1.0000
4:122927756:GAG:G	donor_gain	1.0000
4:122933427:A:AG	acceptor_gain	1.0000
4:122933428:T:G	acceptor_gain	1.0000
4:122933435:A:AG	acceptor_gain	1.0000
4:122933435:ACAGT:A	acceptor_gain	1.0000
4:122933436:C:G	acceptor_gain	1.0000
4:122933437:A:AG	acceptor_gain	1.0000
4:122933437:AGT:A	acceptor_gain	1.0000
4:122933438:G:A	acceptor_loss	1.0000
4:122933438:G:GA	acceptor_gain	1.0000
4:122933438:GT:G	acceptor_gain	1.0000
4:122933438:GTG:G	acceptor_gain	1.0000
4:122933438:GTGA:G	acceptor_gain	1.0000
4:122933438:GTGAC:G	acceptor_gain	1.0000
4:122933493:ACTAG:A	donor_gain	1.0000
4:122933494:CTAG:C	donor_gain	1.0000
4:122933494:CTAGG:C	donor_loss	1.0000
4:122933495:TAGGT:T	donor_loss	1.0000
4:122933496:AGG:A	donor_loss	1.0000
4:122933497:GGTGA:G	donor_loss	1.0000
4:122933498:G:GG	donor_gain	1.0000
4:122933499:T:G	donor_loss	1.0000
4:122934095:A:AG	acceptor_gain	1.0000
4:122934096:G:GG	acceptor_gain	1.0000

AlphaMissense

5820 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:123028337:A:T	K674I	0.998
4:122935765:A:T	K400I	0.996
4:122935782:G:C	A406P	0.996
4:122938221:T:C	L477P	0.996
4:122938230:T:C	L480P	0.995
4:123056433:T:A	V709D	0.995
4:122935768:C:T	T401I	0.994
4:122935777:C:A	A404D	0.994
4:122936126:T:C	L435S	0.994
4:122936129:G:C	R436P	0.994
4:122938152:A:T	E454V	0.994
4:122938166:T:C	C459R	0.994
4:123056412:T:A	V702D	0.994
4:123090623:T:C	L753P	0.994
4:122935747:G:A	G394D	0.993
4:122936108:G:A	G429D	0.993
4:122936137:T:C	F439L	0.993
4:122936139:T:A	F439L	0.993
4:122936139:T:G	F439L	0.993
4:122936146:G:C	A442P	0.993
4:122947276:G:C	R501P	0.993
4:122947303:G:C	R510P	0.993
4:122947315:G:C	R514P	0.993
4:123028338:A:C	K674N	0.993
4:123028338:A:T	K674N	0.993
4:122935746:G:C	G394R	0.992
4:122935762:G:A	G399E	0.992
4:122938160:G:C	A457P	0.992
4:123256036:A:C	R787S	0.992
4:123256036:A:T	R787S	0.992

dbSNP variants (sampled 300 via entrez): RS1000017911 (4:123125932 C>A,T), RS1000024896 (4:122973920 C>T), RS1000024986 (4:123159039 T>G), RS1000038670 (4:123067962 G>A,T), RS1000038816 (4:123212173 T>C,G), RS1000043247 (4:123285391 T>C,G), RS1000048076 (4:123204524 A>G), RS1000052343 (4:123304089 G>A), RS1000071662 (4:123045312 T>A,C), RS1000072524 (4:122942718 T>C,G), RS1000073587 (4:123114776 G>A,C), RS10000771 (4:123213659 G>C,T), RS1000079940 (4:123075679 C>T), RS1000096963 (4:123296816 C>G), RS1000119353 (4:123305667 T>C)

Disease associations

OMIM: gene MIM:613940 | disease phenotypes: MIM:616577, MIM:617577

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic complex neurodevelopmental disorder	Definitive	AR

Mondo (4): microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (MONDO:0014698), syndromic complex neurodevelopmental disorder (MONDO:0800439), neurodevelopmental disorder (MONDO:0700092), ciliary dyskinesia, primary, 37 (MONDO:0033204)

Orphanet (1): Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (Orphanet:457351)

HPO phenotypes

66 total (30 of 66 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000407	Sensorineural hearing impairment
HP:0000430	Underdeveloped nasal alae
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000639	Nystagmus
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000817	Reduced eye contact
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001319	Neonatal hypotonia
HP:0001344	Absent speech
HP:0001508	Failure to thrive
HP:0001631	Atrial septal defect
HP:0001873	Thrombocytopenia
HP:0002019	Constipation
HP:0002020	Gastroesophageal reflux
HP:0002069	Bilateral tonic-clonic seizure
HP:0002079	Hypoplasia of the corpus callosum
HP:0002120	Cerebral cortical atrophy
HP:0002121	Generalized non-motor (absence) seizure
HP:0002123	Generalized myoclonic seizure
HP:0002188	Delayed CNS myelination
HP:0002283	Global brain atrophy

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST002782_12	Waist-to-hip ratio adjusted for body mass index	3.000000e-07
GCST002782_13	Waist-to-hip ratio adjusted for body mass index	4.000000e-08
GCST002782_14	Waist-to-hip ratio adjusted for body mass index	5.000000e-06
GCST002782_15	Waist-to-hip ratio adjusted for body mass index	3.000000e-07
GCST003226_11	Pelvic organ prolapse	2.000000e-06
GCST004505_109	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	8.000000e-06
GCST004861_55	Itch intensity from mosquito bite	2.000000e-11
GCST004861_56	Itch intensity from mosquito bite	1.000000e-10
GCST004862_188	Itch intensity from mosquito bite adjusted by bite size	2.000000e-06
GCST004863_137	Mosquito bite size	2.000000e-07
GCST004863_138	Mosquito bite size	4.000000e-11
GCST007304_2	Reduced foot dorsiflexion strength in Charcot-Marie-Tooth disease type 1A	8.000000e-07
GCST009391_1195	Metabolite levels	5.000000e-06
GCST011408_1	Concussion	1.000000e-10
GCST012227_1295	Hip circumference adjusted for BMI	2.000000e-09
GCST90020024_684	A body shape index	4.000000e-08
GCST90020024_685	A body shape index	3.000000e-11
GCST90020024_686	A body shape index	5.000000e-12
GCST90020025_615	Waist-to-hip ratio adjusted for BMI	2.000000e-11
GCST90020025_616	Waist-to-hip ratio adjusted for BMI	1.000000e-11
GCST90020027_1941	Waist-hip index	4.000000e-08
GCST90020027_1942	Waist-hip index	9.000000e-11
GCST90020027_1943	Waist-hip index	2.000000e-11
GCST90020029_1112	Waist circumference adjusted for body mass index	3.000000e-08
GCST90020029_1113	Waist circumference adjusted for body mass index	9.000000e-11

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004318	smoking behavior
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0009765	alanine measurement
EFO:0011023	concussion
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2311230 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	decreases expression	1
alpha phellandrene	decreases expression	1
glycidyl methacrylate	increases expression	1
arsenite	decreases reaction, affects binding	1
butyraldehyde	decreases expression	1
Bortezomib	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Arsenic	increases abundance, increases expression	1
Cadmium	increases abundance, increases expression	1
Calcitriol	decreases expression, affects cotreatment	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Testosterone	affects cotreatment, decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	increases abundance, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2317269	Binding	Inhibition of SPATA5 (unknown origin) at 10 uM	Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice