Microcytic anemia

Summary

Microcytic anemia (MONDO:0001245) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 104

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcytic anemia
Mondo ID	MONDO:0001245
DOID	DOID:11252
ICD-11	1380406043
NCIT	C35141
SNOMED CT	234349007
UMLS	C5194182
MedGen	1673948
Is cancer (heuristic)	no

Data availability: 104 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › microcytic anemia

Related subtypes (18): congenital anemia, neonatal anemia, hypochromic anemia, pancytopenia, deficiency anemia, pure red-cell aplasia, macrocytic anemia, normocytic anemia, sideroblastic anemia, aplastic anemia, hemoglobin C disease, hemoglobin E disease, beta-thalassemia and related diseases, hemoglobinopathy Toms River, hereditary methemoglobinemia, hemoglobin D disease, anemia due to enzyme disorder, anemia due to chronic disorder

Subtypes (3): hypochromic microcytic anemia, fetal erythroblastosis, IRIDA syndrome

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

104 retrieved; paginated sample, class counts are floors:

44 uncertain significance, 24 benign, 17 conflicting classifications of pathogenicity, 8 benign/likely benign, 6 pathogenic, 3 likely benign, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
523295	GRCh37/hg19 Xq28(chrX:153138672-153665655)	ARHGAP4	Pathogenic	criteria provided, single submitter
1676588	NM_001258392.3(CLPB):c.1588G>A (p.Gly530Arg)	CLPB	Pathogenic	criteria provided, multiple submitters, no conflicts
1408	NM_001374504.1(TMPRSS6):c.1768C>T (p.Arg590Ter)	TMPRSS6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617552	NM_001374504.1(TMPRSS6):c.207C>G (p.Tyr69Ter)	TMPRSS6	Pathogenic	criteria provided, single submitter
627580	NM_001374504.1(TMPRSS6):c.2134C>T (p.Gln712Ter)	TMPRSS6	Pathogenic	criteria provided, single submitter
917402	NM_001374504.1(TMPRSS6):c.336+2T>G	TMPRSS6	Pathogenic	no assertion criteria provided
917403	NM_001374504.1(TMPRSS6):c.1310_1315del (p.Arg437_Val438del)	TMPRSS6	Pathogenic	no assertion criteria provided
1404	NM_001374504.1(TMPRSS6):c.1534G>A (p.Asp512Asn)	TMPRSS6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
262727	NM_001374504.1(TMPRSS6):c.2356G>A (p.Val786Ile)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341581	NM_001374504.1(TMPRSS6):c.2058C>G (p.Phe686Leu)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341584	NM_001374504.1(TMPRSS6):c.1493C>T (p.Pro498Leu)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341588	NM_001374504.1(TMPRSS6):c.1206C>T (p.Gly402=)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341591	NM_001374504.1(TMPRSS6):c.992C>T (p.Thr331Met)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341593	NM_001374504.1(TMPRSS6):c.882G>A (p.Ala294=)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341594	NM_001374504.1(TMPRSS6):c.838G>T (p.Val280Leu)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341597	NM_001374504.1(TMPRSS6):c.632-8C>T	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341598	NM_001374504.1(TMPRSS6):c.589+9T>C	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341602	NM_001374504.1(TMPRSS6):c.411A>G (p.Gly137=)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341603	NM_001374504.1(TMPRSS6):c.243C>A (p.Gly81=)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899477	NM_001374504.1(TMPRSS6):c.1440C>T (p.Cys480=)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899546	NM_001374504.1(TMPRSS6):c.406G>A (p.Glu136Lys)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900680	NM_001374504.1(TMPRSS6):c.307C>T (p.Arg103Cys)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900683	NM_001374504.1(TMPRSS6):c.212C>T (p.Ala71Val)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900684	NM_001374504.1(TMPRSS6):c.183G>A (p.Val61=)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903166	NM_001374504.1(TMPRSS6):c.549G>A (p.Arg183=)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030290	NM_001374504.1(TMPRSS6):c.1085C>T (p.Thr362Met)	TMPRSS6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030292	NM_001374504.1(TMPRSS6):c.827T>G (p.Leu276Arg)	TMPRSS6	Uncertain significance	criteria provided, multiple submitters, no conflicts
341572	NM_001374504.1(TMPRSS6):c.*499C>T	TMPRSS6	Uncertain significance	criteria provided, single submitter
341573	NM_001374504.1(TMPRSS6):c.*303T>G	TMPRSS6	Uncertain significance	criteria provided, single submitter
341574	NM_001374504.1(TMPRSS6):c.*140C>T	TMPRSS6	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMPRSS6	Orphanet:209981	IRIDA syndrome
CLPB	Orphanet:445038	3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome
CLPB	Orphanet:486	Autosomal dominant severe congenital neutropenia

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
TMPRSS6	HGNC:16517	ENSG00000187045	Q8IU80	Transmembrane protease serine 6	clinvar
CLPB	HGNC:30664	ENSG00000162129	Q9H078	Mitochondrial disaggregase	clinvar
ARHGAP4	HGNC:674	ENSG00000089820	P98171	Rho GTPase-activating protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMPRSS6	Transmembrane protease serine 6	Membrane-bound serine protease.
CLPB	Mitochondrial disaggregase	Functions as a regulatory ATPase and participates in secretion/protein trafficking process.
ARHGAP4	Rho GTPase-activating protein 4	Inhibitory effect on stress fiber organization.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

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
Scaffold/PPI	2	11.5×	0.019
Protease	1	12.2×	0.080

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMPRSS6	Protease	yes	3.4.21.109	SEA_dom, CUB_dom, Trypsin_dom
CLPB	Scaffold/PPI	no		ClpA/B, Ankyrin_rpt, AAA+_ATPase
ARHGAP4	Scaffold/PPI	no		RhoGAP_dom, FCH_dom, SH3_domain

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
liver	1
mammary duct	1
right lobe of liver	1
left testis	1
right testis	1
sperm	1
granulocyte	1
monocyte	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMPRSS6	142	tissue_specific	yes	right lobe of liver, liver, mammary duct
CLPB	205	ubiquitous	marker	sperm, left testis, right testis
ARHGAP4	229	broad	marker	granulocyte, spleen, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLPB	5,095
ARHGAP4	1,088
TMPRSS6	897

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLPB	Q9H078	7
TMPRSS6	Q8IU80	1
ARHGAP4	P98171	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Collagen degradation	1	87.8×	0.032	TMPRSS6
Degradation of the extracellular matrix	1	58.9×	0.032	TMPRSS6
RHOA GTPase cycle	1	37.3×	0.032	ARHGAP4
CDC42 GTPase cycle	1	36.1×	0.032	ARHGAP4
RAC1 GTPase cycle	1	30.5×	0.032	ARHGAP4

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
RIG-I signaling pathway	1	802.5×	0.013	CLPB
negative regulation of fibroblast migration	1	510.7×	0.013	ARHGAP4
self proteolysis	1	510.7×	0.013	TMPRSS6
granulocyte differentiation	1	401.2×	0.013	CLPB
membrane protein proteolysis	1	351.1×	0.013	TMPRSS6
negative regulation of axon extension	1	244.2×	0.014	ARHGAP4
regulation of synapse assembly	1	234.1×	0.014	ARHGAP4
multicellular organismal-level iron ion homeostasis	1	193.7×	0.015	TMPRSS6
collagen catabolic process	1	130.6×	0.018	TMPRSS6
extracellular matrix disassembly	1	122.1×	0.018	TMPRSS6
cellular response to heat	1	114.6×	0.018	CLPB
negative regulation of BMP signaling pathway	1	96.8×	0.020	TMPRSS6
Rho protein signal transduction	1	82.6×	0.020	ARHGAP4
intracellular iron ion homeostasis	1	81.4×	0.020	TMPRSS6
antiviral innate immune response	1	75.9×	0.020	CLPB
BMP signaling pathway	1	66.9×	0.021	TMPRSS6
regulation of small GTPase mediated signal transduction	1	48.0×	0.028	ARHGAP4
cytoskeleton organization	1	44.2×	0.029	ARHGAP4
negative regulation of cell migration	1	37.2×	0.032	ARHGAP4
nervous system development	1	15.3×	0.074	ARHGAP4
negative regulation of DNA-templated transcription	1	10.5×	0.101	TMPRSS6
negative regulation of transcription by RNA polymerase II	1	5.9×	0.167	TMPRSS6
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	TMPRSS6

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
TMPRSS6	0	0
CLPB	0	0
ARHGAP4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TMPRSS6	21	Binding:21

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TMPRSS6	3.4.21.109	matriptase

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	1	TMPRSS6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CLPB, ARHGAP4

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)
TMPRSS6	21	—
CLPB	0	—
ARHGAP4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.