PPP1R21

Summary

PPP1R21 (protein phosphatase 1 regulatory subunit 21, HGNC:30595) is a protein-coding gene on chromosome 2p16.3, encoding Protein phosphatase 1 regulatory subunit 21 (Q6ZMI0). Component of the FERRY complex (Five-subunit Endosomal Rab5 and RNA/ribosome intermediary).

Enables RNA binding activity. Located in early endosome.

Source: NCBI Gene 129285 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities (Definitive, GenCC)
• GWAS associations: 12
• Clinical variants (ClinVar): 242 total — 15 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 62
• MANE Select transcript: NM_001135629

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30595
Approved symbol	PPP1R21
Name	protein phosphatase 1 regulatory subunit 21
Location	2p16.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ16566, Fy-2, FERRY2
Ensembl gene	ENSG00000162869
Ensembl biotype	protein_coding
OMIM	618159
Entrez	129285

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 15 protein_coding, 3 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000281394, ENST00000294952, ENST00000416913, ENST00000421486, ENST00000431614, ENST00000449090, ENST00000455978, ENST00000460299, ENST00000476199, ENST00000892709, ENST00000892710, ENST00000892711, ENST00000892712, ENST00000892713, ENST00000942808, ENST00000942809, ENST00000942810, ENST00000942811, ENST00000942812, ENST00000942813

RefSeq mRNA: 3 — MANE Select: NM_001135629 NM_001135629, NM_001193475, NM_152994

CCDS: CCDS1839, CCDS46278, CCDS54358

Canonical transcript exons

ENST00000294952 — 22 exons

Exon	Start	End
ENSE00001430616	48440766	48441010
ENSE00003465474	48505564	48505596
ENSE00003466470	48454595	48454741
ENSE00003468858	48458126	48458227
ENSE00003471207	48471279	48471367
ENSE00003487644	48479924	48480016
ENSE00003526052	48514715	48515386
ENSE00003559875	48465493	48465642
ENSE00003570886	48510015	48510113
ENSE00003573882	48460095	48460153
ENSE00003593201	48474683	48474819
ENSE00003595803	48495679	48495771
ENSE00003609593	48507269	48507385
ENSE00003630200	48464937	48464989
ENSE00003640871	48491018	48491170
ENSE00003656510	48471087	48471188
ENSE00003657705	48459754	48459918
ENSE00003668766	48486631	48486758
ENSE00003674228	48511340	48511468
ENSE00003676286	48498493	48498735
ENSE00003684317	48461138	48461232
ENSE00003688308	48451008	48451076

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 96.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.6442 / max 354.1431, expressed in 1690 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20183	5.4883	1648
20184	0.9280	416
202187	0.2280	93

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	96.66	gold quality
germinal epithelium of ovary	UBERON:0001304	96.37	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.73	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.28	gold quality
parietal pleura	UBERON:0002400	94.22	gold quality
primary visual cortex	UBERON:0002436	94.06	gold quality
tibia	UBERON:0000979	93.50	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.42	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.39	gold quality
visceral pleura	UBERON:0002401	93.08	gold quality
right frontal lobe	UBERON:0002810	93.08	gold quality
body of uterus	UBERON:0009853	92.98	gold quality
myometrium	UBERON:0001296	92.94	gold quality
corpus callosum	UBERON:0002336	92.91	gold quality
occipital lobe	UBERON:0002021	92.84	gold quality
substantia nigra	UBERON:0002038	92.67	gold quality
right lobe of thyroid gland	UBERON:0001119	92.62	gold quality
anterior cingulate cortex	UBERON:0009835	92.53	gold quality
cerebral cortex	UBERON:0000956	92.52	gold quality
Ammon’s horn	UBERON:0001954	92.51	gold quality
amygdala	UBERON:0001876	92.46	gold quality
frontal cortex	UBERON:0001870	92.43	gold quality
neocortex	UBERON:0001950	92.39	gold quality
prefrontal cortex	UBERON:0000451	92.37	gold quality
epithelium of nasopharynx	UBERON:0001951	92.33	gold quality
nasopharynx	UBERON:0001728	92.31	gold quality
lower esophagus	UBERON:0013473	92.31	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.31	gold quality
putamen	UBERON:0001874	92.28	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.99
E-GEOD-124858	no	168.21

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

78 targeting PPP1R21, 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-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-186-5P	99.99	70.83	3707
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607

Literature-anchored findings (GeneRIF, showing 4)

• Although PPP1R21 has not yet been linked to human disease, the consistency in the phenotype of individuals from unrelated families, the nature of the variants which result in truncated proteins, and the expected vital role for PPP1R21 in cellular function, all support that PPP1R21 is a novel disease-associated gene responsible for the phenotype observed in these individuals (PMID:29808498)
• a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway, is reported. (PMID:30520571)
• A Homozygous PPP1R21 Splice Variant Associated with Severe Developmental Delay, Absence of Speech, and Muscle Weakness Leads to Activated Proteasome Function. (PMID:36692708)
• Expanding the phenotype of PPP1R21-related neurodevelopmental disorder. (PMID:38356149)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppp1r21	ENSDARG00000103144
mus_musculus	Ppp1r21	ENSMUSG00000034709
rattus_norvegicus	Ppp1r21	ENSRNOG00000016528
drosophila_melanogaster	CG6607	FBGN0039204
caenorhabditis_elegans		WBGENE00018011

Protein

Protein identifiers

Protein phosphatase 1 regulatory subunit 21 — Q6ZMI0 (reviewed: Q6ZMI0)

Alternative names: Coiled-coil domain-containing protein 128, Ferry endosomal RAB5 effector complex subunit 2, KLRAQ motif-containing protein 1

All UniProt accessions (5): Q6ZMI0, F8W7E1, F8WBY8, F8WE40, H7C1Y1

UniProt curated annotations — full annotation on UniProt →

Function. Component of the FERRY complex (Five-subunit Endosomal Rab5 and RNA/ribosome intermediary). The FERRY complex directly interacts with mRNAs and RAB5A, and functions as a RAB5A effector involved in the localization and the distribution of specific mRNAs most likely by mediating their endosomal transport. The complex recruits mRNAs and ribosomes to early endosomes through direct mRNA-interaction. In the complex, PPP1R21 serves as a binding hub connecting all five complex subunits and mediating the binding to mRNA and early endosomes via RAB5A. Putative regulator of protein phosphatase 1 (PP1) activity. May play a role in the endosomal sorting process or in endosome maturation pathway.

Subunit / interactions. Component of the FERRY complex, composed of five subunits: TBCK, PPP1R21, FERRY3, CRYZL1 and GATAD1, with a ratio of 1:2:1:2:4 respectively. PPP1R21 serves as a binding hub connecting all five complex subunits to mediate the binding to specific mitochondrial mRNAs. Interacts with the GTP-bound form of RAB5A (via its C-terminal region); linking the mRNP complex onto trafficking endosomes for active mRNA transport. Interacts with PPP1CA.

Subcellular location. Early endosome.

Disease relevance. Neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities (NEDHFBA) [MIM:619383] An autosomal recessive disorder characterized by global developmental delay, severely impaired intellectual development, hypotonia, coarse facial features, and muscle weakness, often resulting in the inability to walk or sit. Additional features include feeding difficulties, respiratory distress, scoliosis, poor visual function, and rotary nystagmus. Brain imaging shows variable abnormalities, including enlarged ventricles, decreased white matter volume, white matter changes, thin corpus callosum, and cerebellar hypoplasia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Coiled-coil domains of PPP1R21 are essential for RNA binding.

Isoforms (5)

UniProt ID	Names	Canonical?
Q6ZMI0-1	1	yes
Q6ZMI0-2	2
Q6ZMI0-5	5
Q6ZMI0-3	3
Q6ZMI0-4	4

RefSeq proteins (3): NP_001129101, NP_001180404, NP_694539 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019343	PPP1R21_N	Domain
IPR019348	PPP1R21_six_helix	Domain
IPR040024	PPP1R21	Family
IPR049372	PPP1R21_C	Domain

Pfam: PF10205, PF10212, PF21636

UniProt features (24 total): sequence variant 8, splice variant 5, sequence conflict 3, coiled-coil region 3, region of interest 2, chain 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7ND2	ELECTRON MICROSCOPY	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZMI0-F1	83.89	0.56

Functional residue map

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

Post-translational modifications (1): 652

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 358 (showing top): TGCACTT_MIR519C_MIR519B_MIR519A, GATA3_01, GATA1_01, RFX1_02, GOBP_RNA_LOCALIZATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, ATGTTTC_MIR494, GCCATNTTG_YY1_Q6, RYTGCNWTGGNR_UNKNOWN, GOCC_EARLY_ENDOSOME_MEMBRANE, SCGGAAGY_ELK1_02, MGGAAGTG_GABP_B, GOMF_MRNA_BINDING, ATGGYGGA_UNKNOWN, GCACTTT_MIR175P_MIR20A_MIR106A_MIR106B_MIR20B_MIR519D

GO Biological Process (1): regulation of intracellular mRNA localization (GO:1904580)

GO Molecular Function (4): RNA binding (GO:0003723), mRNA binding (GO:0003729), protein-macromolecule adaptor activity (GO:0030674), protein binding (GO:0005515)

GO Cellular Component (4): early endosome (GO:0005769), membrane (GO:0016020), early endosome membrane (GO:0031901), endosome (GO:0005768)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular mRNA localization	1
regulation of localization	1
nucleic acid binding	1
RNA binding	1
protein binding	1
molecular adaptor activity	1
binding	1
endosome	1
cellular anatomical structure	1
early endosome	1
endosome membrane	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

654 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPP1R21	STON1	Q9Y6Q2	610
PPP1R21	Q53S48	Q53S48	572
PPP1R21	CCDC188	H7C350	571
PPP1R21	FERRY3	Q9NQ89	566
PPP1R21	FOXN2	P32314	513
PPP1R21	TBCK	Q8TEA7	503
PPP1R21	MRPL41	Q8IXM3	489
PPP1R21	MFSD11	O43934	480
PPP1R21	STPG4	Q8N801	477
PPP1R21	CCDC149	Q6ZUS6	474
PPP1R21	MAPRE3	Q9UPY8	473
PPP1R21	NOAZFP	Q9Y3S2	449
PPP1R21	DRC8	Q5VUJ9	446
PPP1R21	KRABD5	Q7Z2F6	431
PPP1R21	STRN	O43815	428

IntAct

46 interactions, top by confidence:

A	B	Type	Score
PPP1R21	FERRY3	psi-mi:“MI:0407”(direct interaction)	0.790
FERRY3	CRYZL1	psi-mi:“MI:0915”(physical association)	0.690
PPP1R21	CRYZL1	psi-mi:“MI:0407”(direct interaction)	0.590
PPP1R21	TBCK	psi-mi:“MI:0407”(direct interaction)	0.590
GATD1	CRYZL1	psi-mi:“MI:0915”(physical association)	0.570
THBS2	AP1G2	psi-mi:“MI:0914”(association)	0.530
FBXL14	CRYZL1	psi-mi:“MI:0914”(association)	0.530
WDTC1	TCP1	psi-mi:“MI:0914”(association)	0.530
TCP10L	CRYZL1	psi-mi:“MI:0914”(association)	0.530
PPP1R21	RAB5A	psi-mi:“MI:0407”(direct interaction)	0.520
PPP1R21	KLHL24	psi-mi:“MI:0915”(physical association)	0.500
PPP1R21	SH2D2A	psi-mi:“MI:0915”(physical association)	0.490
PPP1R21	PPP1CA	psi-mi:“MI:0407”(direct interaction)	0.440
PPP1R21	PDIA3	psi-mi:“MI:0915”(physical association)	0.400
GATD1		psi-mi:“MI:0915”(physical association)	0.400
PPP1R21	CFTR	psi-mi:“MI:0915”(physical association)	0.370
PPP1R21	SH3GL2	psi-mi:“MI:0915”(physical association)	0.370
Tbck	FAM20B	psi-mi:“MI:0914”(association)	0.350
PPP1R21		psi-mi:“MI:0914”(association)	0.350
PB2		psi-mi:“MI:0914”(association)	0.350
APBB1	SSPOP	psi-mi:“MI:0914”(association)	0.350
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
RAB5A	CRYZL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (90): PPP1R21 (Two-hybrid), CRYZL1 (Affinity Capture-MS), PIBF1 (Affinity Capture-MS), PPP1R21 (Two-hybrid), PPP1R21 (Proximity Label-MS), FEN1 (Affinity Capture-MS), MYBPH (Affinity Capture-MS), TAF6 (Affinity Capture-MS), TOX4 (Affinity Capture-MS), CRYZL1 (Affinity Capture-MS), CEP162 (Affinity Capture-MS), ERC1 (Affinity Capture-MS), MRPL18 (Affinity Capture-MS), NDUFAF1 (Affinity Capture-MS), C12orf4 (Affinity Capture-MS)

ESM2 similar proteins: A0JNT9, A1IH00, A2AUM9, A7MD70, B8JK76, B9EKI3, D3YV10, G9G127, O35550, O35551, P0CB05, P55937, P82094, Q08378, Q08379, Q13136, Q15276, Q3TDD9, Q502I3, Q5BIX7, Q5EE04, Q5T1M5, Q5TZ80, Q5U3A8, Q5U4E6, Q5VU43, Q5ZJ27, Q62839, Q66KE8, Q6NRB0, Q6P132, Q6P3P1, Q6P402, Q6P9Q6, Q6PGZ0, Q6VGS5, Q6ZMI0, Q7SXE4, Q80UF4, Q80YT7

Diamond homologs: Q3TDD9, Q5U3A8, Q5ZL12, Q6IR70, Q6ZMI0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	6
Uncertain significance	155
Likely benign	31
Benign	3

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1174145	NM_001135629.3(PPP1R21):c.427C>T (p.Arg143Ter)	Pathogenic
1174146	NM_001135629.3(PPP1R21):c.87_88del (p.Gly30fs)	Pathogenic
1174147	NM_001135629.3(PPP1R21):c.347del (p.Ile116fs)	Pathogenic
1174148	NM_001135629.3(PPP1R21):c.2170_2171insGGTA (p.Ile724fs)	Pathogenic
1174149	NM_001135629.3(PPP1R21):c.1607dup (p.Leu536fs)	Pathogenic
1174150	NM_001135629.3(PPP1R21):c.193C>T (p.Arg65Ter)	Pathogenic
2149078	NM_001135629.3(PPP1R21):c.1981G>T (p.Glu661Ter)	Pathogenic
2171576	NM_001135629.3(PPP1R21):c.310C>T (p.Gln104Ter)	Pathogenic
2302092	NM_001135629.3(PPP1R21):c.415G>T (p.Glu139Ter)	Pathogenic
2637432	NM_001135629.3(PPP1R21):c.1868C>G (p.Ser623Ter)	Pathogenic
3393501	NM_001135629.3(PPP1R21):c.1950del (p.Arg651fs)	Pathogenic
3393502	NM_001135629.3(PPP1R21):c.2096T>C (p.Leu699Pro)	Pathogenic
3393503	NM_001135629.3(PPP1R21):c.224T>G (p.Leu75Arg)	Pathogenic
3393505	NM_001135629.3(PPP1R21):c.748-3A>G	Pathogenic
870419	NM_001135629.3(PPP1R21):c.2063del (p.Lys688fs)	Pathogenic
1174144	NM_001135629.3(PPP1R21):c.2089C>T (p.Arg697Ter)	Likely pathogenic
1333266	NM_001135629.3(PPP1R21):c.1171del (p.Lys390_Met391insTer)	Likely pathogenic
2572420	NM_001135629.3(PPP1R21):c.126+2T>C	Likely pathogenic
2584981	NM_001135629.3(PPP1R21):c.763del (p.Ile255fs)	Likely pathogenic
3586721	NM_001135629.3(PPP1R21):c.463C>T (p.Gln155Ter)	Likely pathogenic
844226	NM_001135629.3(PPP1R21):c.541-2A>G	Likely pathogenic

SpliceAI

3787 predictions. Top by Δscore:

Variant	Effect	Δscore
2:48448567:C:G	donor_gain	1.0000
2:48451006:A:AG	acceptor_gain	1.0000
2:48451007:G:GG	acceptor_gain	1.0000
2:48451072:TAAAG:T	donor_loss	1.0000
2:48451073:AAAG:A	donor_loss	1.0000
2:48451074:AAGGT:A	donor_loss	1.0000
2:48451075:AG:A	donor_loss	1.0000
2:48451076:GGTG:G	donor_loss	1.0000
2:48451077:GTG:G	donor_loss	1.0000
2:48451078:T:G	donor_loss	1.0000
2:48454587:T:TA	acceptor_gain	1.0000
2:48454593:A:AG	acceptor_gain	1.0000
2:48454594:G:GG	acceptor_gain	1.0000
2:48454594:GGA:G	acceptor_gain	1.0000
2:48454594:GGAGC:G	acceptor_gain	1.0000
2:48454737:ACAAG:A	donor_gain	1.0000
2:48454739:AAGG:A	donor_loss	1.0000
2:48454740:AG:A	donor_gain	1.0000
2:48454741:GG:G	donor_gain	1.0000
2:48454742:G:GG	donor_gain	1.0000
2:48454742:GTAG:G	donor_loss	1.0000
2:48454743:T:G	donor_loss	1.0000
2:48458124:A:AC	acceptor_loss	1.0000
2:48458124:A:AG	acceptor_gain	1.0000
2:48458125:G:GA	acceptor_gain	1.0000
2:48458125:G:GT	acceptor_loss	1.0000
2:48458125:GA:G	acceptor_gain	1.0000
2:48458125:GAAA:G	acceptor_gain	1.0000
2:48458125:GAAAA:G	acceptor_gain	1.0000
2:48458224:ACAAG:A	donor_loss	1.0000

AlphaMissense

5132 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:48451009:T:C	L20P	1.000
2:48451030:T:C	L27P	1.000
2:48454658:T:C	F64L	1.000
2:48454659:T:C	F64S	1.000
2:48454660:T:A	F64L	1.000
2:48454660:T:G	F64L	1.000
2:48454674:T:C	L69P	1.000
2:48511401:T:C	L749P	1.000
2:48440994:C:A	A14D	0.999
2:48451012:G:C	R21P	0.999
2:48451034:A:C	K28N	0.999
2:48451034:A:T	K28N	0.999
2:48454626:G:C	R53T	0.999
2:48454627:A:C	R53S	0.999
2:48454627:A:T	R53S	0.999
2:48454649:A:C	S61R	0.999
2:48454651:T:A	S61R	0.999
2:48454651:T:G	S61R	0.999
2:48454659:T:G	F64C	0.999
2:48454662:G:C	R65P	0.999
2:48454695:T:C	L76P	0.999
2:48458187:T:C	L112P	0.999
2:48511380:T:C	L742S	0.999
2:48511389:T:C	M745T	0.999
2:48511391:A:C	S746R	0.999
2:48511393:T:A	S746R	0.999
2:48511393:T:G	S746R	0.999
2:48511397:C:G	H748D	0.999
2:48511398:A:C	H748P	0.999
2:48440991:T:C	L13P	0.998

dbSNP variants (sampled 300 via entrez): RS1000011858 (2:48515073 A>G), RS1000047171 (2:48501288 T>C,G), RS1000067848 (2:48471327 A>G), RS1000075352 (2:48503299 T>G), RS1000097345 (2:48454034 G>A), RS1000117641 (2:48491293 TGGTG>T), RS1000123926 (2:48504271 A>G), RS1000145825 (2:48441457 A>G,T), RS1000157227 (2:48441662 A>C,G), RS1000177804 (2:48472873 C>G,T), RS1000178530 (2:48507585 T>C), RS1000228425 (2:48476649 A>G,T), RS1000230776 (2:48507729 T>C,G), RS1000273237 (2:48467216 T>C), RS1000309555 (2:48477682 T>C)

Disease associations

OMIM: gene MIM:618159 | disease phenotypes: MIM:619383

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities	Strong	AR

Mondo (1): neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities (MONDO:0859165)

Orphanet (0):

HPO phenotypes

62 total (30 of 62 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000270	Delayed cranial suture closure
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000331	Short chin
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000431	Wide nasal bridge
HP:0000446	Narrow nasal bridge
HP:0000463	Anteverted nares
HP:0000506	Telecanthus
HP:0000545	Myopia
HP:0000565	Esotropia
HP:0000574	Thick eyebrow
HP:0000582	Upslanted palpebral fissure
HP:0000592	Blue sclerae
HP:0000648	Optic atrophy
HP:0000768	Pectus carinatum
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001284	Areflexia
HP:0001320	Cerebellar vermis hypoplasia
HP:0001357	Plagiocephaly
HP:0001371	Flexion contracture

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST003496_13	Educational attainment	3.000000e-10
GCST003998_16	Joint mobility (Beighton score)	1.000000e-07
GCST004619_11	Reticulocyte fraction of red cells	8.000000e-10
GCST004639_23	Prudent dietary pattern	5.000000e-06
GCST004865_62	Itch intensity from mosquito bite adjusted by bite size	5.000000e-06
GCST005992_27	Mean corpuscular hemoglobin concentration	6.000000e-09
GCST007552_33	Colorectal cancer	1.000000e-08
GCST007576_366	Chronotype	1.000000e-07
GCST90002405_123	Reticulocyte count	6.000000e-11
GCST90002406_15	Reticulocyte fraction of red cells	4.000000e-12
GCST90011900_138	Serum alkaline phosphatase levels	4.000000e-09
GCST90013406_13	Liver enzyme levels (alkaline phosphatase)	1.000000e-15

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment
EFO:0007905	joint hypermobility measurement
EFO:0007986	reticulocyte count
EFO:0008111	diet measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0008328	chronotype measurement
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression	2
Valproic Acid	increases expression, increases methylation	2
dicrotophos	decreases expression	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	affects expression	1
K 7174	increases expression	1
abrine	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects methylation	1
Caffeine	decreases phosphorylation	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Nickel	decreases expression	1
Quercetin	decreases expression	1
Tretinoin	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TF74	HAP1 PPP1R21 (-) 1	Cancer cell line	Male
CVCL_TF75	HAP1 PPP1R21 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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