Congenital dyserythropoietic anemia type 2

Summary

Congenital dyserythropoietic anemia type 2 (MONDO:0009134) is a disease caused by SEC23B (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: (Europe) [Orphanet-validated]
• Causal gene: SEC23B (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 605

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		377	Europe	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital dyserythropoietic anemia type 2
Mondo ID	MONDO:0009134
OMIM	224100
Orphanet	98873
DOID	DOID:0111401
SNOMED CT	68870007
UMLS	C1306589
MedGen	266296
GARD	0002001
Is cancer (heuristic)	no

Also known as: anemia, congenital dyserythropoietic, type II · anemia, dyserythropoietic, congenital type 2 · CDA II · CDA type 2 · CDA type II · CDAN2 · congenital dyserythropoietic anemia type 2 · dyserythropoietic anemia, congenital, type II · hempas anaemia · hempas anemia · hereditary erythroblastic multinuclearity with a positive acidified-serum test (hempas) · SEC23B-CDG

Data availability: 605 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › congenital dyserythropoietic anemia type 2

Related subtypes (7): myopathy, lactic acidosis, and sideroblastic anemia, congenital nonspherocytic hemolytic anemia, congenital dyserythropoietic anemia type 3, congenital dyserythropoietic anemia type 4, severe congenital hypochromic anemia with ringed sideroblasts, Fanconi anemia, congenital dyserythropoietic anemia type 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

342 likely benign, 93 uncertain significance, 47 pathogenic, 40 conflicting classifications of pathogenicity, 27 likely pathogenic, 21 benign, 16 pathogenic/likely pathogenic, 14 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1227	NM_006363.6(SEC23B):c.649C>T (p.Arg217Ter)	LOC126862987	Pathogenic	criteria provided, multiple submitters, no conflicts
1686174	NM_006363.6(SEC23B):c.367C>T (p.Arg123Ter)	LOC126862987	Pathogenic	criteria provided, multiple submitters, no conflicts
2152326	NM_006363.6(SEC23B):c.490del (p.Val164fs)	LOC126862987	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2922899	NM_006363.6(SEC23B):c.689+1G>C	LOC126862987	Pathogenic	criteria provided, single submitter
2925646	NM_006363.6(SEC23B):c.568C>T (p.Arg190Ter)	LOC126862987	Pathogenic	criteria provided, multiple submitters, no conflicts
2939603	NM_006363.6(SEC23B):c.689+1G>T	LOC126862987	Pathogenic	criteria provided, single submitter
2944168	NM_006363.6(SEC23B):c.592A>T (p.Lys198Ter)	LOC126862987	Pathogenic	criteria provided, single submitter
463383	NM_006363.6(SEC23B):c.576_583delinsA (p.Thr192_Lys193insTer)	LOC126862987	Pathogenic	criteria provided, single submitter
3248265	NC_000020.10:g.(?17603729)(18541384_?)del	MGME1	Pathogenic	criteria provided, single submitter
1222	NM_006363.6(SEC23B):c.325G>A (p.Glu109Lys)	SEC23B	Pathogenic	criteria provided, multiple submitters, no conflicts
1223	NM_006363.6(SEC23B):c.40C>T (p.Arg14Trp)	SEC23B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1225	NM_006363.6(SEC23B):c.790C>T (p.Arg264Ter)	SEC23B	Pathogenic	criteria provided, multiple submitters, no conflicts
1226	NM_006363.6(SEC23B):c.970C>T (p.Arg324Ter)	SEC23B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1358676	NM_006363.6(SEC23B):c.1603C>T (p.Arg535Ter)	SEC23B	Pathogenic	criteria provided, multiple submitters, no conflicts
1515145	NM_006363.6(SEC23B):c.2101C>T (p.Arg701Cys)	SEC23B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
167667	NM_006363.6(SEC23B):c.1489C>T (p.Arg497Cys)	SEC23B	Pathogenic	criteria provided, multiple submitters, no conflicts
167668	NM_006363.6(SEC23B):c.1648C>T (p.Arg550Ter)	SEC23B	Pathogenic	criteria provided, multiple submitters, no conflicts
1806373	NM_006363.6(SEC23B):c.640C>T (p.Gln214Ter)	SEC23B	Pathogenic	criteria provided, multiple submitters, no conflicts
1978944	NM_006363.6(SEC23B):c.1710dup (p.Arg571Ter)	SEC23B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2199307	NM_006363.6(SEC23B):c.1909del (p.Val637fs)	SEC23B	Pathogenic	criteria provided, single submitter
2433272	NM_006363.6(SEC23B):c.1660del (p.Arg554fs)	SEC23B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2921892	NM_006363.6(SEC23B):c.1402C>T (p.Gln468Ter)	SEC23B	Pathogenic	criteria provided, single submitter
2921906	NM_006363.6(SEC23B):c.2190_2191dup (p.Asn731fs)	SEC23B	Pathogenic	criteria provided, single submitter
2922469	NM_006363.6(SEC23B):c.873del (p.Phe291fs)	SEC23B	Pathogenic	criteria provided, single submitter
2922725	NM_006363.6(SEC23B):c.835-2A>G	SEC23B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2923149	NM_006363.6(SEC23B):c.235C>T (p.Arg79Ter)	SEC23B	Pathogenic	criteria provided, single submitter
2924090	NC_000020.11:g.18512225_18512228del	SEC23B	Pathogenic	criteria provided, single submitter
2925278	NM_006363.6(SEC23B):c.1015C>T (p.Arg339Ter)	SEC23B	Pathogenic	criteria provided, multiple submitters, no conflicts
2925647	NM_006363.6(SEC23B):c.938G>A (p.Arg313His)	SEC23B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2925648	NM_006363.6(SEC23B):c.953T>C (p.Ile318Thr)	SEC23B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SEC23B	Definitive	Autosomal recessive	congenital dyserythropoietic anemia type 2	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SEC23B	Orphanet:201	Cowden syndrome
SEC23B	Orphanet:98873	Congenital dyserythropoietic anemia type II
MGME1	Orphanet:352447	Progressive external ophthalmoplegia-myopathy-emaciation syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SEC23B	HGNC:10702	ENSG00000101310	Q15437	Protein transport protein Sec23B	gencc,clinvar
POLR3F	HGNC:15763	ENSG00000132664	Q9H1D9	DNA-directed RNA polymerase III subunit RPC6	clinvar
MGME1	HGNC:16205	ENSG00000125871	Q9BQP7	Mitochondrial genome maintenance exonuclease 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SEC23B	Protein transport protein Sec23B	Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).
POLR3F	DNA-directed RNA polymerase III subunit RPC6	DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.
MGME1	Mitochondrial genome maintenance exonuclease 1	Metal-dependent single-stranded DNA (ssDNA) exonuclease involved in mitochondrial genome maintenance.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SEC23B	Transcription factor	no		Znf_Sec23_Sec24, Sec23/24_trunk_dom, Sec23/24_helical_dom
POLR3F	Other/Unknown	no		RNA_pol_Rpc34, RNA_pol_Rpc34-like, WH-like_DNA-bd_sf
MGME1	Other/Unknown	no		Restrct_endonuc-II-like, PDDEXK-like_dom_sf, PDDEXK_AddAB-type

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	1
islet of Langerhans	1
parotid gland	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SEC23B	289	ubiquitous	marker	endothelial cell, islet of Langerhans, parotid gland
POLR3F	221	ubiquitous	yes	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
MGME1	250	ubiquitous	marker	upper arm skin, left ventricle myocardium, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SEC23B	2,460
POLR3F	1,892
MGME1	1,121

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR3F	Q9H1D9	31
MGME1	Q9BQP7	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SEC23B	Q15437	92.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Strand-asynchronous mitochondrial DNA replication	1	571.0×	0.010	MGME1
RNA Polymerase III Chain Elongation	1	317.2×	0.010	POLR3F
RNA Polymerase III Transcription Termination	1	248.3×	0.010	POLR3F
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	211.5×	0.010	POLR3F
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	203.9×	0.010	POLR3F
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	203.9×	0.010	POLR3F
RNA Polymerase III Transcription Initiation	1	167.9×	0.010	POLR3F
RNA Polymerase III Transcription	1	163.1×	0.010	POLR3F
Cytosolic sensors of pathogen-associated DNA	1	142.8×	0.010	POLR3F
RNA Polymerase III Abortive And Retractive Initiation	1	139.3×	0.010	POLR3F
DNA Replication	1	119.0×	0.011	MGME1
Innate Immune System	1	12.8×	0.090	POLR3F
Gene expression (Transcription)	1	8.9×	0.117	POLR3F
Immune System	1	6.5×	0.148	POLR3F

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial DNA repair	1	802.5×	0.007	MGME1
regulation of transcription by RNA polymerase III	1	561.7×	0.007	POLR3F
mitochondrial DNA replication	1	510.7×	0.007	MGME1
COPII-coated vesicle cargo loading	1	330.4×	0.008	SEC23B
transcription by RNA polymerase III	1	255.3×	0.008	POLR3F
positive regulation of innate immune response	1	175.5×	0.009	POLR3F
positive regulation of interferon-beta production	1	130.6×	0.011	POLR3F
defense response to virus	1	23.1×	0.051	POLR3F
intracellular protein transport	1	21.6×	0.051	SEC23B
innate immune response	1	11.2×	0.087	POLR3F

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SEC23B	0	0
POLR3F	0	0
MGME1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SEC23B	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SEC23B, POLR3F, MGME1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SEC23B	1	—
POLR3F	0	—
MGME1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.