acrofacial dysostosis Cincinnati type

Summary

acrofacial dysostosis Cincinnati type (MONDO:0014651) is a disease caused by POLR1A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: POLR1A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 41

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	acrofacial dysostosis Cincinnati type
Mondo ID	MONDO:0014651
OMIM	616462
DOID	DOID:0060353
UMLS	C4225317
MedGen	903483
GARD	0016117
Is cancer (heuristic)	no

Also known as: acrofacial dysostosis caused by mutation in POLR1A · acrofacial dysostosis, Cincinnati type · AFDCIN · POLR1A acrofacial dysostosis

Data availability: 41 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › acrofacial dysostosis › acrofacial dysostosis Cincinnati type

Related subtypes (13): acrofacial dysostosis, Catania type, Patterson-Stevenson-Fontaine syndrome, acrofacial dysostosis, Weyers type, acrocraniofacial dysostosis, acrofacial dysostosis Rodriguez type, acrofrontofacionasal dysostosis, postaxial acrofacial dysostosis, acrofacial dysostosis, Palagonia type, acromelic frontonasal dysostosis, mandibulofacial dysostosis-microcephaly syndrome, acrofacial dysostosis, Kennedy-Teebi type, acrofacial dysostosis Preis type, SF3B4-related acrofacial dysostosis

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

41 retrieved; paginated sample, class counts are floors:

22 uncertain significance, 7 benign, 5 conflicting classifications of pathogenicity, 3 pathogenic, 3 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
203463	NM_015425.6(POLR1A):c.1777G>C (p.Glu593Gln)	LOC126806264	Pathogenic	no assertion criteria provided
203464	NM_015425.6(POLR1A):c.3649del (p.Gln1217fs)	POLR1A	Pathogenic	no assertion criteria provided
626284	NM_015425.6(POLR1A):c.2527C>T (p.Arg843Ter)	POLR1A	Pathogenic	no assertion criteria provided
2500796	NM_015425.6(POLR1A):c.190del (p.Cys64fs)	POLR1A	Likely pathogenic	criteria provided, single submitter
421393	NM_015425.6(POLR1A):c.4685G>T (p.Cys1562Phe)	POLR1A	Likely pathogenic	criteria provided, single submitter
4688021	NM_015425.6(POLR1A):c.2164C>T (p.Arg722Ter)	POLR1A	Likely pathogenic	criteria provided, single submitter
1395840	NM_015425.6(POLR1A):c.4451G>A (p.Arg1484Gln)	POLR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1502342	NM_015425.6(POLR1A):c.3418G>A (p.Ala1140Thr)	POLR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2778175	NM_015425.6(POLR1A):c.978G>A (p.Val326=)	POLR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
421169	NM_015425.6(POLR1A):c.3988_3990del (p.Glu1330del)	POLR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
774163	NM_015425.6(POLR1A):c.1511G>A (p.Arg504His)	POLR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2431838	NM_015425.6(POLR1A):c.1612-3dup	LOC126806264	Uncertain significance	criteria provided, single submitter
2435153	NM_015425.6(POLR1A):c.1846C>T (p.Gln616Ter)	LOC126806264	Uncertain significance	criteria provided, single submitter
1029398	NM_015425.6(POLR1A):c.4034+1G>T	POLR1A	Uncertain significance	criteria provided, single submitter
1333986	NM_015425.6(POLR1A):c.1543C>T (p.Arg515Ter)	POLR1A	Uncertain significance	criteria provided, single submitter
1918076	NM_015425.6(POLR1A):c.4421C>T (p.Pro1474Leu)	POLR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1969766	NM_015425.6(POLR1A):c.2986C>A (p.Leu996Ile)	POLR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2084670	NM_015425.6(POLR1A):c.1106C>G (p.Ala369Gly)	POLR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2198814	NM_015425.6(POLR1A):c.1031T>C (p.Leu344Ser)	POLR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435154	NM_015425.6(POLR1A):c.4501C>T (p.Arg1501Trp)	POLR1A	Uncertain significance	criteria provided, single submitter
2720730	NM_015425.6(POLR1A):c.4357A>G (p.Arg1453Gly)	POLR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
3216426	NM_015425.6(POLR1A):c.2002G>C (p.Val668Leu)	POLR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
3254637	NM_015425.6(POLR1A):c.965A>G (p.Asn322Ser)	POLR1A	Uncertain significance	criteria provided, single submitter
3255114	NM_015425.6(POLR1A):c.818G>T (p.Gly273Val)	POLR1A	Uncertain significance	criteria provided, single submitter
3586944	NM_015425.6(POLR1A):c.1463C>A (p.Pro488His)	POLR1A	Uncertain significance	criteria provided, single submitter
3586945	NM_015425.6(POLR1A):c.1380+4T>G	POLR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
3777208	NM_015425.6(POLR1A):c.1139G>C (p.Gly380Ala)	POLR1A	Uncertain significance	criteria provided, single submitter
3781702	NM_015425.6(POLR1A):c.4708A>C (p.Asn1570His)	POLR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
4056749	NM_015425.6(POLR1A):c.4345C>T (p.Arg1449Ter)	POLR1A	Uncertain significance	criteria provided, single submitter
4079771	NM_015425.6(POLR1A):c.1504G>A (p.Gly502Ser)	POLR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 1 · 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
POLR1A	Strong	Autosomal dominant	acrofacial dysostosis Cincinnati type	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLR1A	Orphanet:1200	Burn-McKeown syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POLR1A	HGNC:17264	ENSG00000068654	O95602	DNA-directed RNA polymerase I subunit RPA1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLR1A	DNA-directed RNA polymerase I subunit RPA1	Catalytic core component of RNA polymerase I (Pol I), a DNA-dependent RNA polymerase which synthesizes ribosomal RNA precursors using the four ribonucleoside triphosphates as substrates.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLR1A	Other/Unknown	no		RNA_pol_asu, RNA_pol_N, RNA_pol_Rpb1_3

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
stromal cell of endometrium	1
sural nerve	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLR1A	198	ubiquitous	marker	sural nerve, tibialis anterior, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR1A	4,620

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR1A	O95602	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Positive epigenetic regulation of rRNA expression	1	346.1×	0.008	POLR1A
RNA Polymerase I Transcription Termination	1	326.3×	0.008	POLR1A
RNA Polymerase I Promoter Clearance	1	292.8×	0.008	POLR1A
RNA Polymerase I Transcription	1	285.5×	0.008	POLR1A
Negative epigenetic regulation of rRNA expression	1	259.6×	0.008	POLR1A
RNA Polymerase I Transcription Initiation	1	223.9×	0.008	POLR1A
B-WICH complex positively regulates rRNA expression	1	121.5×	0.011	POLR1A
RNA Polymerase I Promoter Escape	1	121.5×	0.011	POLR1A
NoRC negatively regulates rRNA expression	1	104.8×	0.012	POLR1A
Epigenetic regulation of gene expression	1	71.4×	0.015	POLR1A
Gene expression (Transcription)	1	17.8×	0.056	POLR1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of protein localization to nucleolus	1	5617.3×	4e-04	POLR1A
nucleolar large rRNA transcription by RNA polymerase I	1	3370.4×	4e-04	POLR1A
transcription by RNA polymerase I	1	1404.3×	7e-04	POLR1A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLR1A	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	POLR1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
POLR1A	16	Binding:16

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	POLR1A

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	1	POLR1A
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.