CARMIL2

Summary

CARMIL2 (capping protein regulator and myosin 1 linker 2, HGNC:27089) is a protein-coding gene on chromosome 16q22.1, encoding Capping protein, Arp2/3 and myosin-I linker protein 2 (Q6F5E8). Cell membrane-cytoskeleton-associated protein that plays a role in the regulation of actin polymerization at the barbed end of actin filaments.

This gene encodes a member of the CARMIL (capping protein, Arp2/3, myosin-I linker) family of proteins. The encoded protein interacts with and negatively regulates the heterodimeric capping protein and promotes cell migration. Reduced expression of this gene has been observed in human psoriasis patients. Mutations in this gene cause a human immunodeficiency syndrome characterized by smooth muscle tumors and impaired T-cell function.

Source: NCBI Gene 146206 — RefSeq curated summary.

At a glance

• Gene–disease (curated): severe combined immunodeficiency due to CARMIL2 deficiency (Definitive, ClinGen)
• GWAS associations: 4
• Clinical variants (ClinVar): 1,241 total — 52 pathogenic, 24 likely-pathogenic
• Phenotypes (HPO): 42
• MANE Select transcript: NM_001013838

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27089
Approved symbol	CARMIL2
Name	capping protein regulator and myosin 1 linker 2
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	LRRC16C
Ensembl gene	ENSG00000159753
Ensembl biotype	protein_coding
OMIM	610859
Entrez	146206

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 7 retained_intron, 5 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000334583, ENST00000545661, ENST00000602321, ENST00000602368, ENST00000602467, ENST00000602562, ENST00000602563, ENST00000602633, ENST00000602705, ENST00000602742, ENST00000602924, ENST00000602931, ENST00000696044, ENST00000696045, ENST00000696175, ENST00000696176

RefSeq mRNA: 2 — MANE Select: NM_001013838 NM_001013838, NM_001317026

CCDS: CCDS45513, CCDS81998

Canonical transcript exons

ENST00000334583 — 38 exons

Exon	Start	End
ENSE00001337679	67656228	67656299
ENSE00001337772	67656031	67656067
ENSE00001337773	67654778	67654900
ENSE00001337774	67654332	67654692
ENSE00001746585	67648052	67648314
ENSE00003304989	67645144	67645286
ENSE00003420264	67653019	67653254
ENSE00003476418	67647116	67647191
ENSE00003577359	67656424	67656645
ENSE00003580462	67654149	67654249
ENSE00003965880	67657406	67657569
ENSE00003966317	67657239	67657316
ENSE00003966319	67646900	67646973
ENSE00003966320	67646426	67646517
ENSE00003966322	67652199	67652339
ENSE00003966323	67656801	67656881
ENSE00003966324	67649254	67649311
ENSE00003966326	67649447	67649619
ENSE00003966327	67645724	67645777
ENSE00003966329	67651187	67651315
ENSE00003966330	67649076	67649172
ENSE00003966332	67651685	67651845
ENSE00003966333	67648685	67648754
ENSE00003966334	67648398	67648502
ENSE00003966335	67647508	67647602
ENSE00003966336	67647680	67647766
ENSE00003966337	67647299	67647387
ENSE00003966338	67646018	67646080
ENSE00003966339	67649806	67649968
ENSE00003966341	67650049	67650150
ENSE00003966342	67645540	67645631
ENSE00003966343	67651921	67652008
ENSE00003966344	67648893	67648974
ENSE00003966345	67647846	67647958
ENSE00003966346	67646714	67646784
ENSE00003966348	67651401	67651514
ENSE00003966349	67646186	67646310
ENSE00003966350	67652472	67652538

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 94.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.2185 / max 229.1759, expressed in 992 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154671	3.0496	719
154668	1.7908	294
154669	1.7467	213
154667	0.4146	224
154670	0.1763	71
207919	0.0405	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	94.02	gold quality
anterior cingulate cortex	UBERON:0009835	93.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.30	gold quality
cerebellar hemisphere	UBERON:0002245	92.75	gold quality
granulocyte	CL:0000094	92.71	gold quality
cerebellar cortex	UBERON:0002129	92.71	gold quality
prefrontal cortex	UBERON:0000451	91.77	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.69	gold quality
amygdala	UBERON:0001876	91.43	gold quality
putamen	UBERON:0001874	91.37	gold quality
cerebellum	UBERON:0002037	91.34	gold quality
nucleus accumbens	UBERON:0001882	91.18	gold quality
lymph node	UBERON:0000029	90.94	gold quality
spleen	UBERON:0002106	90.86	gold quality
vermiform appendix	UBERON:0001154	90.43	gold quality
caudate nucleus	UBERON:0001873	90.37	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.31	gold quality
hypothalamus	UBERON:0001898	88.98	gold quality
frontal cortex	UBERON:0001870	88.77	gold quality
neocortex	UBERON:0001950	88.74	gold quality
Ammon’s horn	UBERON:0001954	87.15	gold quality
cerebral cortex	UBERON:0000956	86.95	gold quality
forebrain	UBERON:0001890	86.81	gold quality
brain	UBERON:0000955	86.51	gold quality
bone marrow cell	CL:0002092	85.80	gold quality
cortical plate	UBERON:0005343	85.42	gold quality
caecum	UBERON:0001153	85.24	gold quality
kidney epithelium	UBERON:0004819	84.83	gold quality
adenohypophysis	UBERON:0002196	84.44	gold quality
pituitary gland	UBERON:0000007	83.58	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.22

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 15)

• On the basis of these results, we propose a model in which dynamic vimentin filaments target CARMIL2 to critical membrane-associated locations, where CARMIL2 regulates CP, and thus actin assembly, to create cell protrusions (PMID:26466680)
• Data suggest that CARMIL2 displays two localization patterns in cells; one coincides with vimentin intermediate filaments, and the other coincides with cell membrane at leading edge of migrating cells. (PMID:26578515)
• the scaffolding role of RLTPR predominates during CD28 co-stimulation and underpins the similar function of RLTPR in human and mouse T cells. (PMID:27647348)
• Human RLTPR deficiency is a Combined immunodeficiency affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells. (PMID:27647349)
• These cases showed that CARMIL2-deficiency is an autosomal recessive primary immunodeficiency disorder associated with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics. (PMID:28112205)
• RLTPR (p.Q575E) increases binding of RLTPR to downstream components of the NF-kappaB signaling pathway, selectively upregulates the NF-kappaB pathway in activated T cells. (PMID:28694326)
• this study reports three patients with a recently described combined immunodeficiency disorder, CARMIL2-deficiency, bearing a novel homozygous mutation on splice-acceptor site region on CARMIL2-gene (PMID:31001706)
• This case provides evidence that CARMIL2 should be a candidate gene when diagnosing children with very early onset inflammatory and eosinophilic gastrointestinal disorders, even when signs of immunodeficiency are not observed. (PMID:31079270)
• The study highlights that human CARMIL2 deficiency can manifest with inflammatory bowel diseases (IBD)-like symptoms. (PMID:31115454)
• Synaptic actin stabilization protein loss in Down syndrome and Alzheimer disease. (PMID:31410926)
• Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation. (PMID:32201938)
• A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors. (PMID:32625199)
• RLTPR Q575E: A novel recurrent gain-of-function mutation in patients with adult T-cell leukemia/lymphoma. (PMID:33098696)
• Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease. (PMID:33723309)
• Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency. (PMID:36515678)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Carmil2	ENSMUSG00000050357
rattus_norvegicus	Carmil2	ENSRNOG00000024452
drosophila_melanogaster	LRR	FBGN0033212
caenorhabditis_elegans	crml-1	WBGENE00010641

Paralogs (4): RNH1 (ENSG00000023191), CARMIL1 (ENSG00000079691), PPP1R37 (ENSG00000104866), CARMIL3 (ENSG00000186648)

Protein

Protein identifiers

Capping protein, Arp2/3 and myosin-I linker protein 2 — Q6F5E8 (reviewed: Q6F5E8)

Alternative names: Capping protein regulator and myosin 1 linker 2, F-actin-uncapping protein RLTPR, Leucine-rich repeat-containing protein 16C, RGD, leucine-rich repeat, tropomodulin and proline-rich-containing protein

All UniProt accessions (6): Q6F5E8, A0A8Q3SIB7, A0A8Q3SII9, A0A8Q3WKY0, A0A8Q3WLI1, R4GNC4

UniProt curated annotations — full annotation on UniProt →

Function. Cell membrane-cytoskeleton-associated protein that plays a role in the regulation of actin polymerization at the barbed end of actin filaments. Prevents F-actin heterodimeric capping protein (CP) activity at the leading edges of migrating cells, and hence generates uncapped barbed ends and enhances actin polymerization. Plays a role in cell protrusion formations; involved in cell polarity, lamellipodial assembly, membrane ruffling and macropinosome formations. Involved as well in cell migration and invadopodia formation during wound healing. Required for CD28-mediated stimulation of NF-kappa-B signaling, involved in naive T cells activation, maturation into T memory cells, and differentiation into T helper and T regulatory cells.

Subunit / interactions. Forms homodimers. Interacts (via C-terminus) with heterodimeric capping protein (CP); the interaction inhibits CP activity and hence promotes actin polymerization at the barbed end of actin filaments.

Subcellular location. Cytoplasm. Cytoskeleton. Cell membrane. Cell projection. Lamellipodium. Ruffle.

Tissue specificity. Expressed in all tissues tested, including thymus, spleen, colon, leukocytes, peripheral blood, skin, skin keratinocytes and skin fibroblasts. Strong expression is detected in naive and memory CD4+ and CD8+ T cells, naive and memory B cells, regulatory T cells and NK cells, whereas it is poorly expressed in monocytes.

Disease relevance. Immunodeficiency 58 (IMD58) [MIM:618131] An autosomal recessive primary immunodeficiency characterized by a variety of infectious diseases, including mycobacterial diseases, mucocutaneous candidiasis, silent but detectable EBV viremia, and staphylococcal diseases. Patients suffer from dermatitis, esophagitis, recurrent skin abscesses and chest infections. Immunologic analysis shows defective T-cell function and deficient CD3/CD28 stimulation responses in both CD4+ and CD8+ T cells. B-cell function may also be impaired. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal leucine-rich repeat (LRR) domain is necessary for localization to vimentin filaments. The C-terminus is necessary for localization to the cell membrane.

Similarity. Belongs to the CARMIL family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6F5E8-1	1, CARMIL2a	yes
Q6F5E8-2	2, CARMIL2b

RefSeq proteins (2): NP_001013860, NP_001303955 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR031943	CARMIL_C	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR041245	CARMIL_PH	Domain
IPR051279	PP1-Reg/Actin-Interact_Protein	Family

Pfam: PF13516, PF16000, PF17888

UniProt features (47 total): repeat 16, compositionally biased region 8, modified residue 7, sequence variant 5, mutagenesis site 5, region of interest 3, splice variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6F5E8-F1	61.50	0.12

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 (7): 991, 993, 1120, 1246, 1303, 1315, 1420

Mutagenesis-validated functional residues (5):

Position	Phenotype
1021	loss of ability to bind heterodimeric capping protein (cp), unable to inhibit the actin-capping activity of cp and to re
1023	loss of ability to bind heterodimeric capping protein (cp), unable to inhibit the actin-capping activity of cp and to re
1096–1106	loss of accumulation at the cell membrane. does not alter colocalization at vimentin filaments. alters monopolar cell po

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 259 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_MONOPOLAR_CELL_POLARITY, chr16q22, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_REGULATION_OF_ACTIN_NUCLEATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_BARBED_END_ACTIN_FILAMENT_CAPPING, GOBP_REGULATION_OF_RUFFLE_ASSEMBLY, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_DEPOLYMERIZATION, GOCC_RUFFLE, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_DISASSEMBLY

GO Biological Process (12): establishment or maintenance of cell polarity (GO:0007163), positive regulation of lamellipodium assembly (GO:0010592), cell migration (GO:0016477), positive regulation of cell migration (GO:0030335), regulation of Arp2/3 complex-mediated actin nucleation (GO:0034315), wound healing, spreading of cells (GO:0044319), actin filament network formation (GO:0051639), establishment or maintenance of monopolar cell polarity (GO:0061339), positive regulation of extracellular matrix disassembly (GO:0090091), positive regulation of ruffle assembly (GO:1900029), positive regulation of lamellipodium organization (GO:1902745), negative regulation of barbed-end actin filament capping (GO:2000813)

GO Molecular Function (3): phospholipid binding (GO:0005543), protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (12): ruffle (GO:0001726), cytoplasm (GO:0005737), plasma membrane (GO:0005886), actin cytoskeleton (GO:0015629), membrane (GO:0016020), lamellipodium (GO:0030027), extrinsic component of cytoplasmic side of plasma membrane (GO:0031234), cell leading edge (GO:0031252), macropinosome (GO:0044354), intermediate filament cytoskeleton (GO:0045111), cytoskeleton (GO:0005856), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
positive regulation of plasma membrane bounded cell projection assembly	2
cell migration	2
binding	2
cell leading edge	2
plasma membrane bounded cell projection	2
cytoskeleton	2
cellular process	1
regulation of lamellipodium assembly	1
lamellipodium assembly	1
positive regulation of lamellipodium organization	1
cell motility	1
regulation of cell migration	1
positive regulation of cell motility	1
Arp2/3 complex-mediated actin nucleation	1
regulation of actin nucleation	1
epiboly involved in wound healing	1
actin filament organization	1
establishment or maintenance of cell polarity	1
regulation of extracellular matrix disassembly	1
extracellular matrix disassembly	1
positive regulation of extracellular matrix organization	1
ruffle assembly	1
regulation of ruffle assembly	1
positive regulation of cell projection organization	1
lamellipodium organization	1
regulation of lamellipodium organization	1
positive regulation of actin filament depolymerization	1
positive regulation of actin filament polymerization	1
barbed-end actin filament capping	1
negative regulation of cellular component organization	1
regulation of barbed-end actin filament capping	1
lipid binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
cytoplasmic side of plasma membrane	1
extrinsic component of plasma membrane	1
pinosome	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

588 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CARMIL2	TMOD4	Q9NZQ9	899
CARMIL2	TMOD2	Q9NZR1	882
CARMIL2	TMOD3	Q9NYL9	847
CARMIL2	TMOD1	P28289	845
CARMIL2	CD28	P10747	765
CARMIL2	TTK	P33981	763
CARMIL2	NFKBIL1	Q9UBC1	650
CARMIL2	CARD11	Q9BXL7	609
CARMIL2	DOCK8	Q8NF50	571
CARMIL2	CTPS1	P17812	476
CARMIL2	MAGT1	Q9H0U3	444
CARMIL2	WASHC2C	Q9Y4E1	408
CARMIL2	THAP12	O43422	405
CARMIL2	LRBA	P50851	398
CARMIL2	RCSD1	Q6JBY9	390

IntAct

27 interactions, top by confidence:

A	B	Type	Score
MED7	MED19	psi-mi:“MI:0914”(association)	0.840
CAPZB	CNOT1	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
CARMIL2	CAPZA1	psi-mi:“MI:0915”(physical association)	0.400
CARMIL2	IQGAP3	psi-mi:“MI:0915”(physical association)	0.400
NOTCH1	CNOT1	psi-mi:“MI:0914”(association)	0.350
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.350
YWHAH	SHTN1	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	POM121C	psi-mi:“MI:0914”(association)	0.350
CAPZB	ENAH	psi-mi:“MI:0914”(association)	0.350
SLC45A1	TBC1D4	psi-mi:“MI:0914”(association)	0.350
FOXD3	CLUH	psi-mi:“MI:0914”(association)	0.350
CD247	DDX1	psi-mi:“MI:0914”(association)	0.350
NIN	AP3D1	psi-mi:“MI:2364”(proximity)	0.270
YWHAB	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAE	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAH	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAQ	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAZ	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAG	E2F8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (30): RLTPR (Affinity Capture-MS), RLTPR (Proximity Label-MS), RLTPR (Affinity Capture-MS), RLTPR (Proximity Label-MS), RLTPR (Affinity Capture-MS), RLTPR (Affinity Capture-MS), RLTPR (Proximity Label-MS), RLTPR (Affinity Capture-MS), RLTPR (Affinity Capture-MS), CAPZA1 (Affinity Capture-MS), RLTPR (Affinity Capture-MS), RLTPR (Affinity Capture-MS), IQGAP3 (Affinity Capture-MS), RLTPR (Affinity Capture-MS), RLTPR (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PJB7, A0A1L8HX76, A6QR40, O08764, O60294, O95382, P10938, P70218, P97452, Q12851, Q14137, Q15334, Q16586, Q28686, Q32P44, Q3TJ91, Q499N3, Q499U2, Q4KLI9, Q561R2, Q562C2, Q5RBH8, Q5RCX2, Q61161, Q6AY79, Q6F5E8, Q6P1M3, Q6V7V2, Q7SZE3, Q7TMC8, Q80Y17, Q8BYZ7, Q8C3I8, Q8C6B2, Q8CHW4, Q8K4K5, Q8MKF0, Q8N0W3, Q8VC03, Q91WI7

Diamond homologs: Q3UFQ8, Q3V3V9, Q5VZK9, Q5XHY1, Q6EDY6, Q6F5E8, Q8ND23, A0A0G2JTR4, A4II46, A6QNS3, A7KAX9, B0S6J3, B2RTY4, D3ZFJ3, D4A208, E7EZG2, E7F3F0, F1LQX4, F1LXF1, O43295, O75044, P11274, P32873, P42331, P55194, P98171, Q10164, Q12979, Q17R89, Q3KRB8, Q3UIA2, Q54G18, Q54TH9, Q54Y72, Q54YV1, Q559A0, Q55DK5, Q5SSL4, Q5SSM3, Q68EM7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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	6	198.6×	2e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	175.2×	2e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	175.2×	2e-11
Activation of BH3-only proteins	6	129.5×	2e-10
RHO GTPases activate PKNs	6	82.8×	2e-09
Intrinsic Pathway for Apoptosis	6	76.4×	3e-09
Translocation of SLC2A4 (GLUT4) to the plasma membrane	7	47.0×	3e-09
Transcriptional and post-translational regulation of MITF-M expression and activity	6	46.5×	5e-08

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	67.8×	2e-06
intracellular protein localization	7	27.1×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

1241 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	24
Uncertain significance	477
Likely benign	610
Benign	45

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1361069	NM_001013838.3(CARMIL2):c.3650_3663dup (p.Val1222delinsCysArgGlyTer)	Pathogenic
1387358	NM_001013838.3(CARMIL2):c.334_337del (p.Ala112fs)	Pathogenic
1388986	NM_001013838.3(CARMIL2):c.37C>T (p.Arg13Ter)	Pathogenic
1416319	NM_001013838.3(CARMIL2):c.3493C>T (p.Arg1165Ter)	Pathogenic
1452801	NM_001013838.3(CARMIL2):c.4108del (p.Ala1370fs)	Pathogenic
1675629	NM_001013838.3(CARMIL2):c.1109C>A (p.Ser370Ter)	Pathogenic
1701294	NM_001013838.3(CARMIL2):c.887_897delinsTGTTGTCCTG (p.Ser296fs)	Pathogenic
1810230	NM_001013838.3(CARMIL2):c.950dup (p.Pro318fs)	Pathogenic
2007713	NM_001013838.3(CARMIL2):c.1384_1385del (p.Arg462fs)	Pathogenic
2010186	NM_001013838.3(CARMIL2):c.3922C>T (p.Gln1308Ter)	Pathogenic
2029028	NM_001013838.3(CARMIL2):c.3208C>T (p.Gln1070Ter)	Pathogenic
2036608	NM_001013838.3(CARMIL2):c.1894del (p.Ala632fs)	Pathogenic
2122854	NM_001013838.3(CARMIL2):c.868C>T (p.Arg290Ter)	Pathogenic
2162530	NM_001013838.3(CARMIL2):c.1197G>A (p.Trp399Ter)	Pathogenic
266035	NM_001013838.3(CARMIL2):c.490dup (p.Ala164fs)	Pathogenic
266036	NM_001013838.3(CARMIL2):c.871+1G>T	Pathogenic
2728157	NM_001013838.3(CARMIL2):c.1241dup (p.Asn414fs)	Pathogenic
2732215	NM_001013838.3(CARMIL2):c.2833C>T (p.Gln945Ter)	Pathogenic
2766009	NM_001013838.3(CARMIL2):c.393del (p.Thr132fs)	Pathogenic
2768123	NM_001013838.3(CARMIL2):c.1172del (p.Gly391fs)	Pathogenic
2793508	NM_001013838.3(CARMIL2):c.1158del (p.Cys387fs)	Pathogenic
2815982	NM_001013838.3(CARMIL2):c.2665dup (p.Arg889fs)	Pathogenic
2846633	NM_001013838.3(CARMIL2):c.787C>T (p.Arg263Ter)	Pathogenic
2867144	NM_001013838.3(CARMIL2):c.448del (p.Asp150fs)	Pathogenic
2879296	NM_001013838.3(CARMIL2):c.955C>T (p.Arg319Ter)	Pathogenic
2986361	NM_001013838.3(CARMIL2):c.1253dup (p.Gln419fs)	Pathogenic
2987270	NM_001013838.3(CARMIL2):c.1232_1257dup (p.Leu420delinsValTer)	Pathogenic
3616562	NM_001013838.3(CARMIL2):c.3257dup (p.Ala1087fs)	Pathogenic
3623144	NM_001013838.3(CARMIL2):c.1172dup (p.Trp392fs)	Pathogenic
3638233	NM_001013838.3(CARMIL2):c.1633A>T (p.Arg545Ter)	Pathogenic

SpliceAI

5781 predictions. Top by Δscore:

Variant	Effect	Δscore
16:67645776:GG:G	donor_gain	1.0000
16:67645777:GG:G	donor_gain	1.0000
16:67646181:CCTA:C	acceptor_loss	1.0000
16:67646182:CTAG:C	acceptor_loss	1.0000
16:67646284:G:GT	donor_gain	1.0000
16:67646285:A:T	donor_gain	1.0000
16:67646309:GG:G	donor_gain	1.0000
16:67646310:GG:G	donor_gain	1.0000
16:67646311:G:GG	donor_gain	1.0000
16:67646312:T:A	donor_loss	1.0000
16:67646781:G:GG	donor_gain	1.0000
16:67646970:GTCG:G	donor_gain	1.0000
16:67646990:G:GT	donor_gain	1.0000
16:67647000:G:GT	donor_gain	1.0000
16:67647003:G:GT	donor_gain	1.0000
16:67647111:ACCAG:A	acceptor_gain	1.0000
16:67647185:G:GT	donor_gain	1.0000
16:67647188:GCTG:G	donor_gain	1.0000
16:67647189:CTGG:C	donor_loss	1.0000
16:67647190:TGG:T	donor_loss	1.0000
16:67647192:G:A	donor_loss	1.0000
16:67647193:T:G	donor_loss	1.0000
16:67647197:G:GT	donor_gain	1.0000
16:67647384:GGGG:G	donor_gain	1.0000
16:67647385:GGGG:G	donor_gain	1.0000
16:67647498:T:TA	acceptor_gain	1.0000
16:67647506:A:AG	acceptor_gain	1.0000
16:67647507:G:GG	acceptor_gain	1.0000
16:67647507:GA:G	acceptor_gain	1.0000
16:67647507:GAGA:G	acceptor_gain	1.0000

AlphaMissense

9185 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:67649155:C:A	N557K	0.999
16:67649155:C:G	N557K	0.999
16:67649475:C:T	S592F	0.999
16:67649557:C:A	N619K	0.999
16:67649557:C:G	N619K	0.999
16:67649816:T:A	W644R	0.999
16:67649816:T:C	W644R	0.999
16:67649827:C:A	N647K	0.999
16:67649827:C:G	N647K	0.999
16:67654215:T:C	F1063L	0.999
16:67654217:C:A	F1063L	0.999
16:67654217:C:G	F1063L	0.999
16:67648973:C:A	N530K	0.998
16:67648973:C:G	N530K	0.998
16:67649826:A:T	N647I	0.998
16:67654216:T:C	F1063S	0.998
16:67646033:A:C	S68R	0.997
16:67646035:C:A	S68R	0.997
16:67646035:C:G	S68R	0.997
16:67649547:T:A	I616N	0.997
16:67649820:A:T	D645V	0.997
16:67654216:T:G	F1063C	0.997
16:67646031:T:C	F67S	0.996
16:67646741:T:C	L165P	0.996
16:67646940:T:C	F193S	0.996
16:67647129:A:C	S209R	0.996
16:67647131:T:A	S209R	0.996
16:67647131:T:G	S209R	0.996
16:67647160:T:C	F219S	0.996
16:67648918:T:A	I512K	0.996

dbSNP variants (sampled 300 via entrez): RS1000054587 (16:67644222 G>T), RS1000195123 (16:67643622 GATAATA>G,GATA,GATAATAATA,GATAATAATAATA), RS1000746119 (16:67655604 A>C,G), RS1000931162 (16:67645038 A>C), RS1001537597 (16:67648417 G>A,T), RS1001618337 (16:67654102 C>A,G), RS1001619510 (16:67644564 G>C), RS1001672086 (16:67654451 G>A), RS1001795517 (16:67651029 T>C,G), RS1001991774 (16:67643325 T>C), RS1002029117 (16:67644854 G>A), RS1002121242 (16:67649055 C>G,T), RS1002136455 (16:67649536 C>A,T), RS1002257492 (16:67655990 G>A,C), RS1002802133 (16:67652596 T>A,C)

Disease associations

OMIM: gene MIM:610859 | disease phenotypes: MIM:618131, MIM:242300

GenCC curated gene-disease

Disease	Classification	Inheritance
severe combined immunodeficiency due to CARMIL2 deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
severe combined immunodeficiency due to CARMIL2 deficiency	Definitive	AR

Mondo (3): severe combined immunodeficiency due to CARMIL2 deficiency (MONDO:0029134), combined immunodeficiency (MONDO:0015131), autosomal recessive congenital ichthyosis (MONDO:0017265)

Orphanet (3): EBV-induced lymphoproliferative disease due to CARMIL2 deficiency (Orphanet:542301), Combined T and B cell immunodeficiency (Orphanet:101972), Autosomal recessive congenital ichthyosis (Orphanet:281097)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000389	Chronic otitis media
HP:0000964	Eczematoid dermatitis
HP:0000992	Cutaneous photosensitivity
HP:0001051	Seborrheic dermatitis
HP:0001075	Atrophic scars
HP:0001508	Failure to thrive
HP:0001742	Nasal congestion
HP:0002015	Dysphagia
HP:0002028	Chronic diarrhea
HP:0002099	Asthma
HP:0002110	Bronchiectasis
HP:0002205	Recurrent respiratory infections
HP:0002583	Colitis
HP:0002728	Chronic mucocutaneous candidiasis
HP:0002788	Recurrent upper respiratory tract infections
HP:0003193	Allergic rhinitis
HP:0003394	Muscle spasm
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004313	Decreased circulating immunoglobulin concentration
HP:0004322	Short stature
HP:0004469	Chronic bronchitis
HP:0005202	Helicobacter pylori infection
HP:0005419	Decreased T cell activation
HP:0006510	Chronic pulmonary obstruction
HP:0006532	Recurrent pneumonia
HP:0008064	Ichthyosis
HP:0011107	Recurrent aphthous stomatitis
HP:0011463	Childhood onset

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006803_42	Schizophrenia	4.000000e-08
GCST010002_113	Refractive error	2.000000e-14
GCST90002388_170	Lymphocyte count	9.000000e-24
GCST90002404_341	Red cell distribution width	7.000000e-14

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
bisphenol A	increases methylation	1
beta-lapachone	increases expression	1
aflatoxin B2	decreases methylation	1
monomethylarsonous acid	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
bisphenol S	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Fulvestrant	increases methylation	1
Air Pollutants	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Catechin	affects cotreatment, decreases expression	1
Estradiol	increases expression	1
Smoke	decreases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02737384	PHASE2	TERMINATED	Hematopoietic Stem Cells Transplantation in Children With Combined Immunodeficiency (CID)
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses
NCT02915406	Not specified	NO_LONGER_AVAILABLE	cliniMACs HUD for T Cell Depletion
NCT04902807	Not specified	RECRUITING	Conception of a Diagnosis, Prognosis and Therapeutic Decision Tool for Patients With Autoimmunity and Inflammation
NCT06659588	Not specified	RECRUITING	Study of Populations at Risk of Developing Chronic Hepatitis Linked to Chronic Enteric Virus Infection in Patients With Primary Immunodeficiency and Secondary Humoral Deficiency
NCT05312073	Not specified	COMPLETED	Study of in Vivo and in Vitro Transcriptomic and Proteomic Signatures in Unhereditary Ichtyosis