methylmalonic aciduria and homocystinuria type cblC

Summary

methylmalonic aciduria and homocystinuria type cblC (MONDO:0010184) is a disease caused by variants in MMACHC and PRDX1, with 7 cohort genes and 1 clinical trial. The dominant Reactome pathway is Defects in cobalamin (B12) metabolism (4 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal genes: MMACHC (GenCC Definitive), PRDX1 (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 589
• Phenotypes (HPO): 76
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		500	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

76 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001889	Megaloblastic anemia	Very frequent (80-99%)
HP:0002160	Hyperhomocystinemia	Very frequent (80-99%)
HP:0002912	Methylmalonic acidemia	Very frequent (80-99%)
HP:0012120	Methylmalonic aciduria	Very frequent (80-99%)
HP:0031544	Elevated propionylcarnitine level	Very frequent (80-99%)
HP:0000206	Glossitis	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000546	Retinal degeneration	Frequent (30-79%)
HP:0000580	Pigmentary retinopathy	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001116	Macular coloboma	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0008002	Abnormality of macular pigmentation	Frequent (30-79%)
HP:0010280	Stomatitis	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0100820	Glomerulopathy	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000707	Abnormality of the nervous system	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000751	Personality changes	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001298	Encephalopathy	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0001644	Dilated cardiomyopathy	Occasional (5-29%)
HP:0001789	Hydrops fetalis	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0001907	Thromboembolism	Occasional (5-29%)
HP:0001943	Hypoglycemia	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0001987	Hyperammonemia	Occasional (5-29%)
HP:0002045	Hypothermia	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002167	Abnormality of speech or vocalization	Occasional (5-29%)
HP:0002352	Leukoencephalopathy	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002625	Deep venous thrombosis	Occasional (5-29%)
HP:0002919	Ketonuria	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	methylmalonic aciduria and homocystinuria type cblC
Mondo ID	MONDO:0010184
OMIM	277400
Orphanet	79282
DOID	DOID:0050715
NCIT	C142174
SNOMED CT	74653006
UMLS	C1848561
MedGen	341256
GARD	0012128
Is cancer (heuristic)	no

Also known as: cblC · cblC defect · cobalamin C defect · cobalamin c disease · combined defect in adenosylcobalamin and methylcobalamin synthesis, type cblC · MAHCC · methylmalonic acidemia and homocystinuria cblC · methylmalonic acidemia with homocystinuria type cblC · methylmalonic aciduria and homocystinuria cblC · methylmalonic aciduria and homocystinuria type cblC · methylmalonic aciduria with homocystinuria, type cblC

Data availability: 589 ClinVar variants · 8 GenCC gene-disease records.

Disease family

Classification path: human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › methylmalonic acidemia › methylmalonic aciduria and homocystinuria › methylmalonic aciduria and homocystinuria type cblC

Related subtypes (5): methylmalonic aciduria and homocystinuria type cblF, methylmalonic aciduria and homocystinuria type cblD, methylmalonic acidemia with homocystinuria, type cblX, methylmalonic acidemia with homocystinuria, type cblJ, methylmalonic aciduria and homocystinuria, cb1L type

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

589 retrieved; paginated sample, class counts are floors:

195 likely benign, 138 uncertain significance, 83 pathogenic, 67 likely pathogenic, 56 pathogenic/likely pathogenic, 39 conflicting classifications of pathogenicity, 6 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1343599	NM_005050.4(ABCD4):c.423C>G (p.Asn141Lys)	ABCD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2691699	NM_005050.4(ABCD4):c.1425dup (p.Tyr476fs)	ABCD4	Pathogenic	criteria provided, single submitter
3902357	NM_005050.4(ABCD4):c.552_564del (p.Gly183_Trp184insTer)	ABCD4	Pathogenic	criteria provided, single submitter
4525942	NM_005050.4(ABCD4):c.529C>T (p.Gln177Ter)	ABCD4	Pathogenic	criteria provided, single submitter
4744293	NM_005050.4(ABCD4):c.1246_1247del (p.Ser416fs)	ABCD4	Pathogenic	criteria provided, multiple submitters, no conflicts
583152	NM_005050.4(ABCD4):c.1588C>T (p.Gln530Ter)	ABCD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070033	NM_018368.4(LMBRD1):c.967_970del (p.Leu323fs)	LMBRD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225048	NM_018368.4(LMBRD1):c.1056del (p.Asn353fs)	LMBRD1	Pathogenic	criteria provided, multiple submitters, no conflicts
517	NM_018368.4(LMBRD1):c.515_516del (p.Thr172fs)	LMBRD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1023220	NM_015506.3(MMACHC):c.643T>C (p.Tyr215His)	LOC129930446	Pathogenic	criteria provided, single submitter
1074542	NM_015506.3(MMACHC):c.649_650del (p.Glu217fs)	LOC129930446	Pathogenic	criteria provided, single submitter
1075815	NM_015506.3(MMACHC):c.599G>A (p.Trp200Ter)	LOC129930446	Pathogenic	criteria provided, multiple submitters, no conflicts
1436751	NM_015506.3(MMACHC):c.600G>A (p.Trp200Ter)	LOC129930446	Pathogenic	criteria provided, multiple submitters, no conflicts
1451201	NM_015506.3(MMACHC):c.647_649del (p.Ser216_Glu217delinsTer)	LOC129930446	Pathogenic	criteria provided, single submitter
1453735	NM_015506.3(MMACHC):c.619del (p.Asp207fs)	LOC129930446	Pathogenic	criteria provided, single submitter
2003636	NM_015506.3(MMACHC):c.648dup (p.Glu217fs)	LOC129930446	Pathogenic	criteria provided, single submitter
203832	NM_015506.3(MMACHC):c.616C>T (p.Arg206Trp)	LOC129930446	Pathogenic	criteria provided, multiple submitters, no conflicts
2121779	NM_015506.3(MMACHC):c.661_664dup (p.Tyr222fs)	LOC129930446	Pathogenic	criteria provided, single submitter
2676632	NM_015506.3(MMACHC):c.634del (p.Gln212fs)	LOC129930446	Pathogenic	criteria provided, multiple submitters, no conflicts
281007	NM_015506.3(MMACHC):c.615C>G (p.Tyr205Ter)	LOC129930446	Pathogenic	criteria provided, multiple submitters, no conflicts
2818364	NM_015506.3(MMACHC):c.614dup (p.Tyr205Ter)	LOC129930446	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2880707	NM_015506.3(MMACHC):c.640dup (p.Arg214fs)	LOC129930446	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30800	NM_015506.3(MMACHC):c.609G>A (p.Trp203Ter)	LOC129930446	Pathogenic	criteria provided, multiple submitters, no conflicts
3650938	NM_015506.3(MMACHC):c.609dup (p.Thr204fs)	LOC129930446	Pathogenic	criteria provided, single submitter
496436	NM_015506.3(MMACHC):c.666C>A (p.Tyr222Ter)	LOC129930446	Pathogenic	criteria provided, multiple submitters, no conflicts
550046	NM_015506.3(MMACHC):c.626_627del (p.Val209fs)	LOC129930446	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
553035	NM_015506.3(MMACHC):c.619dup (p.Asp207fs)	LOC129930446	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
558292	NM_015506.3(MMACHC):c.615C>A (p.Tyr205Ter)	LOC129930446	Pathogenic	criteria provided, multiple submitters, no conflicts
813353	NM_015506.3(MMACHC):c.626dup (p.Thr210fs)	LOC129930446	Pathogenic	criteria provided, multiple submitters, no conflicts
848845	NM_015506.3(MMACHC):c.617G>A (p.Arg206Gln)	LOC129930446	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 8 · 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
MMACHC	Definitive	Autosomal recessive	methylmalonic aciduria and homocystinuria type cblC	7
PRDX1	Strong	Autosomal recessive	methylmalonic aciduria and homocystinuria type cblC

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MMACHC	Orphanet:79282	Methylmalonic acidemia with homocystinuria, type cblC
LMBRD1	Orphanet:79284	Methylmalonic acidemia with homocystinuria type cblF
MMADHC	Orphanet:308380	Methylcobalamin deficiency type cblDv1
MMADHC	Orphanet:308442	Vitamin B12-responsive methylmalonic acidemia, type cblDv2
MMADHC	Orphanet:79283	Methylmalonic acidemia with homocystinuria, type cblD
HCFC1	Orphanet:369962	Methylmalonic acidemia with homocystinuria, type cblX
HCFC1	Orphanet:777	X-linked non-syndromic intellectual disability
ABCD4	Orphanet:369955	Methylmalonic acidemia with homocystinuria, type cblJ

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MMACHC	HGNC:24525	ENSG00000132763	Q9Y4U1	Cyanocobalamin reductase / alkylcobalamin dealkylase	gencc,clinvar
PRDX1	HGNC:9352	ENSG00000117450	Q06830	Peroxiredoxin-1	gencc,clinvar
LMBRD1	HGNC:23038	ENSG00000168216	Q9NUN5	Lysosomal cobalamin transport escort protein LMBD1	clinvar
MMADHC	HGNC:25221	ENSG00000168288	Q9H3L0	Cobalamin trafficking protein CblD	clinvar
DCDC2C	HGNC:32696	ENSG00000214866	A8MYV0	Doublecortin domain-containing protein 2C	clinvar
HCFC1	HGNC:4839	ENSG00000172534	P51610	Host cell factor 1	clinvar
ABCD4	HGNC:68	ENSG00000119688	O14678	Lysosomal cobalamin transporter ABCD4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MMACHC	Cyanocobalamin reductase / alkylcobalamin dealkylase	Cobalamin (vitamin B12) cytosolic chaperone that catalyzes the reductive decyanation of cyanocob(III)alamin (cyanocobalamin, CNCbl) to yield cob(II)alamin and cyanide, using FAD or FMN as cofactors and NADPH as cosubstrate.
PRDX1	Peroxiredoxin-1	Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively.
LMBRD1	Lysosomal cobalamin transport escort protein LMBD1	Lysosomal membrane chaperone required to export cobalamin (vitamin B12) from the lysosome to the cytosol, allowing its conversion to cofactors.
MMADHC	Cobalamin trafficking protein CblD	Involved in cobalamin metabolism and trafficking.
HCFC1	Host cell factor 1	Transcriptional coregulator.
ABCD4	Lysosomal cobalamin transporter ABCD4	Lysosomal membrane protein that transports cobalamin (Vitamin B12) from the lysosomal lumen to the cytosol in an ATP-dependent manner.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.57

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
Transporter	1	11.1×	0.220
Enzyme (other)	2	3.4×	0.220
Antibody/Immunoglobulin	1	4.2×	0.289
Other/Unknown	3	0.8×	0.858

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MMACHC	Enzyme (other)	yes	2.5.1.151	MMACHC
PRDX1	Enzyme (other)	yes	1.11.1.24	AhpC/TSA, Thioredoxin_domain, Peroxiredoxin_C
LMBRD1	Other/Unknown	no		LMBR1-like_membr_prot, LMBD1_LysCbl_Transport
MMADHC	Other/Unknown	no		MMADHC
DCDC2C	Other/Unknown	no		Doublecortin_dom, Doublecortin_dom_sf
HCFC1	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, Kelch-typ_b-propeller
ABCD4	Transporter	yes	7.6.2.8	ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	1
liver	1
right lobe of liver	1
left lobe of thyroid gland	1
nasal cavity epithelium	1
right lobe of thyroid gland	1
oocyte	1
pigmented layer of retina	1
secondary oocyte	1
epithelium of nasopharynx	1
nasopharynx	1
palpebral conjunctiva	1
left testis	1
sural nerve	1
tibial nerve	1
parotid gland	1
skeletal muscle tissue of rectus abdominis	1
tendon of biceps brachii	1
right hemisphere of cerebellum	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MMACHC	177	ubiquitous	marker	right lobe of liver, liver, hindlimb stylopod muscle
PRDX1	295	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, nasal cavity epithelium
LMBRD1	288	ubiquitous	marker	secondary oocyte, oocyte, pigmented layer of retina
MMADHC	294	ubiquitous	marker	palpebral conjunctiva, epithelium of nasopharynx, nasopharynx
DCDC2C	109	tissue_specific	marker	sural nerve, left testis, tibial nerve
HCFC1	274	ubiquitous	marker	tendon of biceps brachii, parotid gland, skeletal muscle tissue of rectus abdominis
ABCD4	259	ubiquitous	marker	right uterine tube, right hemisphere of cerebellum, right ovary

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HCFC1	2,637
MMACHC	1,383
ABCD4	1,327
MMADHC	1,201
PRDX1	798
LMBRD1	609
DCDC2C	365

Intra-cohort edges

A	B	Sources
ABCD4	LMBRD1	intact, string_interaction
ABCD4	MMACHC	string_interaction
ABCD4	MMADHC	string_interaction
LMBRD1	MMACHC	string_interaction
LMBRD1	MMADHC	string_interaction
MMACHC	MMADHC	biogrid_interaction, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRDX1	Q06830	18
HCFC1	P51610	11
MMACHC	Q9Y4U1	7
MMADHC	Q9H3L0	4
ABCD4	O14678	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LMBRD1	Q9NUN5	84.17
DCDC2C	A8MYV0	70.53

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 7 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defects in cobalamin (B12) metabolism	4	543.8×	5e-10	MMACHC, LMBRD1, MMADHC, ABCD4
Cobalamin (Cbl, vitamin B12) transport and metabolism	4	423.0×	7e-10	MMACHC, LMBRD1, MMADHC, ABCD4
Defects in vitamin and cofactor metabolism	4	400.7×	7e-10	MMACHC, LMBRD1, MMADHC, ABCD4
Metabolism of water-soluble vitamins and cofactors	4	120.8×	8e-08	MMACHC, LMBRD1, MMADHC, ABCD4
Metabolism of vitamins and cofactors	4	77.7×	4e-07	MMACHC, LMBRD1, MMADHC, ABCD4
Defective ABCD4 causes MAHCJ	2	1903.3×	1e-06	LMBRD1, ABCD4
Diseases of metabolism	4	53.6×	1e-06	MMACHC, LMBRD1, MMADHC, ABCD4
Defective MMADHC causes MMAHCD	2	1268.9×	2e-06	MMACHC, MMADHC
Transport of RCbl within the body	2	475.8×	2e-05	LMBRD1, ABCD4
Cobalamin (Cbl) metabolism	2	423.0×	2e-05	MMACHC, MMADHC
Uptake of dietary cobalamins into enterocytes	2	380.7×	2e-05	LMBRD1, ABCD4
ABC transporter disorders	2	146.4×	2e-04	LMBRD1, ABCD4
Disease	4	8.7×	9e-04	MMACHC, LMBRD1, MMADHC, ABCD4
Disorders of transmembrane transporters	2	46.4×	0.001	LMBRD1, ABCD4
Metabolism	4	7.7×	0.001	MMACHC, LMBRD1, MMADHC, ABCD4
Defective MMACHC causes MAHCC	1	951.7×	0.002	MMACHC
Scavenging by Class B Receptors	1	173.0×	0.008	PRDX1
NFE2L2 regulating anti-oxidant/detoxification enzymes	1	90.6×	0.015	PRDX1
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	86.5×	0.015	PRDX1
Detoxification of Reactive Oxygen Species	1	50.1×	0.025	PRDX1
Formation of WDR5-containing histone-modifying complexes	1	44.3×	0.027	HCFC1
Transcriptional activation of mitochondrial biogenesis	1	34.0×	0.033	HCFC1
TP53 Regulates Metabolic Genes	1	21.6×	0.049	PRDX1
UCH proteinases	1	20.7×	0.049	HCFC1
HATs acetylate histones	1	13.2×	0.073	HCFC1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cobalamin metabolic process	3	656.6×	3e-07	MMACHC, MMADHC, ABCD4
release from viral latency	1	802.5×	0.014	HCFC1
insulin receptor internalization	1	802.5×	0.014	LMBRD1
demethylation	1	601.9×	0.014	MMACHC
long-chain fatty acid import into peroxisome	1	481.5×	0.014	ABCD4
leukocyte activation	1	481.5×	0.014	PRDX1
very long-chain fatty acid catabolic process	1	343.9×	0.017	ABCD4
cobalamin transport	1	267.5×	0.017	ABCD4
regulation of stress-activated MAPK cascade	1	267.5×	0.017	PRDX1
regulation of non-canonical NF-kappaB signal transduction	1	218.9×	0.018	PRDX1
erythrocyte homeostasis	1	185.2×	0.020	PRDX1
removal of superoxide radicals	1	150.5×	0.020	PRDX1
protein localization to lysosome	1	150.5×	0.020	LMBRD1
peroxisome organization	1	114.6×	0.024	ABCD4
regulation of protein-containing complex assembly	1	104.7×	0.024	HCFC1
gastrulation	1	100.3×	0.024	LMBRD1
hydrogen peroxide catabolic process	1	96.3×	0.024	PRDX1
natural killer cell activation	1	83.0×	0.025	PRDX1
clathrin-dependent endocytosis	1	83.0×	0.025	LMBRD1
blastocyst hatching	1	77.7×	0.026	HCFC1
positive regulation of cell cycle	1	63.4×	0.029	HCFC1
natural killer cell mediated cytotoxicity	1	61.7×	0.029	PRDX1
fibroblast proliferation	1	56.0×	0.030	PRDX1
fatty acid beta-oxidation	1	53.5×	0.030	ABCD4
canonical NF-kappaB signal transduction	1	52.3×	0.030	PRDX1
glutathione metabolic process	1	50.1×	0.030	MMACHC
cell redox homeostasis	1	49.1×	0.030	PRDX1
transmembrane transport	1	24.1×	0.058	ABCD4
cellular response to leukemia inhibitory factor	1	22.7×	0.060	ABCD4
response to oxidative stress	1	18.7×	0.070	PRDX1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 3 of 7 evidence-associated genes (43%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRDX1	1	2
HCFC1	1	2
MMACHC	0	0
LMBRD1	0	0
MMADHC	0	0
DCDC2C	0	0
ABCD4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	HCFC1, PRDX1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
PRDX1	35	Binding:35
HCFC1	8	Binding:8
MMADHC	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MMACHC	2.5.1.151	alkylcobalamin dealkylase
PRDX1	1.11.1.24	thioredoxin-dependent peroxiredoxin
ABCD4	7.6.2.8	ABC-type vitamin B12 transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	HCFC1, PRDX1

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	2	PRDX1, HCFC1
C	Druggable family + PDB, no drug	2	MMACHC, ABCD4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	LMBRD1, MMADHC, DCDC2C

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MMACHC	0	—
LMBRD1	0	—
MMADHC	4	—
DCDC2C	0	—
ABCD4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns