Craniofacial microsomia 1

Summary

Craniofacial microsomia 1 (MONDO:0958175) is a disease caused by SF3B2 (GenCC Strong), with 6 cohort genes.

At a glance

• Causal gene: SF3B2 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	craniofacial microsomia 1
Mondo ID	MONDO:0958175
OMIM	164210
UMLS	C3495417
MedGen	501171
GARD	0026953
Is cancer (heuristic)	no

Data availability: 21 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › craniofacial microsomia › craniofacial microsomia 1

Related subtypes (1): craniofacial microsomia 2

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

21 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 6 pathogenic, 5 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1342664	NM_006842.3(SF3B2):c.2480dup (p.Leu828fs)	LOC130006095	Pathogenic	no assertion criteria provided
1342661	NM_006842.3(SF3B2):c.1780-2del	SF3B2	Pathogenic	no assertion criteria provided
1342662	NM_006842.3(SF3B2):c.1912C>T (p.Arg638Ter)	SF3B2	Pathogenic	no assertion criteria provided
1342663	NM_006842.3(SF3B2):c.1A>T (p.Met1Leu)	SF3B2	Pathogenic	no assertion criteria provided
3254890	NM_006842.3(SF3B2):c.664C>T (p.Arg222Ter)	SF3B2	Pathogenic	criteria provided, single submitter
3383153	NM_006842.3(SF3B2):c.180+2T>C	SF3B2	Pathogenic	criteria provided, single submitter
2430158	NM_001135649.3(FOXI3):c.703C>T (p.Arg235Cys)	FOXI3	Likely pathogenic	no assertion criteria provided
2431343	NM_001135649.3(FOXI3):c.706C>T (p.Arg236Trp)	FOXI3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4082047	NM_006842.3(SF3B2):c.1107dup (p.Glu370Ter)	SF3B2	Likely pathogenic	no assertion criteria provided
4292971	NM_006842.3(SF3B2):c.2101del (p.Glu701fs)	SF3B2	Likely pathogenic	criteria provided, single submitter
1691311	NM_024646.3(ZYG11B):c.628C>T (p.Arg210Ter)	ZYG11B	Likely pathogenic	criteria provided, single submitter
4759497	NM_005483.3(CHAF1A):c.1948-1G>A	CHAF1A	Uncertain significance	no assertion criteria provided
1704311	GRCh37/hg19 4q35.1-35.2(chr4:186473718-187912600)x3	CYP4V2	Uncertain significance	no assertion criteria provided
1353346	NM_001135649.3(FOXI3):c.719G>A (p.Arg240His)	FOXI3	Uncertain significance	criteria provided, single submitter
1986646	NM_001135649.3(FOXI3):c.1105AGCAATAGCACC[1] (p.369SNST[1])	FOXI3	Uncertain significance	criteria provided, single submitter
2431339	NM_001135649.3(FOXI3):c.1243C>T (p.Arg415Ter)	FOXI3	Uncertain significance	criteria provided, single submitter
2431340	NM_001135649.3(FOXI3):c.718C>T (p.Arg240Cys)	FOXI3	Uncertain significance	criteria provided, single submitter
2431341	NM_001135649.3(FOXI3):c.713G>A (p.Arg238Gln)	FOXI3	Uncertain significance	criteria provided, single submitter
2431342	NM_001135649.3(FOXI3):c.707G>A (p.Arg236Gln)	FOXI3	Uncertain significance	criteria provided, single submitter
1162776	NM_002031.3(FRK):c.484G>A (p.Val162Ile)	FRK	Uncertain significance	no assertion criteria provided
3362286	NM_006842.3(SF3B2):c.2321C>T (p.Ala774Val)	SF3B2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
SF3B2	Strong	Autosomal dominant	craniofacial microsomia 1	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP4V2	Orphanet:41751	Bietti crystalline dystrophy

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SF3B2	HGNC:10769	ENSG00000087365	Q13435	Splicing factor 3B subunit 2	gencc,clinvar
CHAF1A	HGNC:1910	ENSG00000167670	Q13111	Chromatin assembly factor 1 subunit A	clinvar
CYP4V2	HGNC:23198	ENSG00000145476	Q6ZWL3	Cytochrome P450 4V2	clinvar
ZYG11B	HGNC:25820	ENSG00000162378	Q9C0D3	Protein zyg-11 homolog B	clinvar
FOXI3	HGNC:35123	ENSG00000214336	A8MTJ6	Forkhead box protein I3	clinvar
FRK	HGNC:3955	ENSG00000111816	P42685	Tyrosine-protein kinase FRK	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SF3B2	Splicing factor 3B subunit 2	Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs.
CHAF1A	Chromatin assembly factor 1 subunit A	Acts as a component of the histone chaperone complex chromatin assembly factor 1 (CAF-1), which assembles histone octamers onto DNA during replication and repair.
CYP4V2	Cytochrome P450 4V2	A cytochrome P450 monooxygenase involved in fatty acid metabolism in the eye.
ZYG11B	Protein zyg-11 homolog B	Serves as substrate adapter subunit in the E3 ubiquitin ligase complex ZYG11B-CUL2-Elongin BC.
FOXI3	Forkhead box protein I3	Transcription factor required for pharyngeal arch development, which is involved in hair, ear, jaw and dental development.
FRK	Tyrosine-protein kinase FRK	Non-receptor tyrosine-protein kinase that negatively regulates cell proliferation.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 3 · 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
Kinase	1	4.6×	0.719
Enzyme (other)	1	2.0×	0.719
Transcription factor	1	1.4×	0.719
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SF3B2	Other/Unknown	no		SAP_dom, PSP_pro-rich, DUF382
CHAF1A	Other/Unknown	no		CAF-1_p150_acidic, CAF1A_DD, CAF1_p150_N
CYP4V2	Enzyme (other)	yes	1.14.14.79	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
ZYG11B	Other/Unknown	no		Leu-rich_rpt, ARM-like, ARM-type_fold
FOXI3	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
FRK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

6 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)	1
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
left testis	1
right testis	1
secondary oocyte	1
sural nerve	1
ileal mucosa	1
kidney epithelium	1
liver	1
deltoid	1
tibialis anterior	1
vastus lateralis	1
male germ line stem cell (sensu Vertebrata) in testis	1
placenta	1
primordial germ cell in gonad	1
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SF3B2	292	ubiquitous	marker	ventricular zone, left testis, right testis
CHAF1A	270	ubiquitous	marker	secondary oocyte, sural nerve, ventricular zone
CYP4V2	254	ubiquitous	marker	kidney epithelium, ileal mucosa, liver
ZYG11B	262	ubiquitous	marker	deltoid, vastus lateralis, tibialis anterior
FOXI3	13	broad	marker	primordial germ cell in gonad, placenta, male germ line stem cell (sensu Vertebrata) in testis
FRK	231	broad	marker	jejunal mucosa, mucosa of sigmoid colon, colonic mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SF3B2	3,906
CHAF1A	2,359
FRK	1,912
CYP4V2	1,867
ZYG11B	988
FOXI3	876

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SF3B2	Q13435	50
ZYG11B	Q9C0D3	14
CHAF1A	Q13111	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP4V2	Q6ZWL3	91.05
FRK	P42685	83.41
FOXI3	A8MTJ6	59.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 6 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
The canonical retinoid cycle in rods (twilight vision)	1	173.0×	0.046	CYP4V2
Endogenous sterols	1	131.3×	0.046	CYP4V2
mRNA Splicing - Minor Pathway	1	74.6×	0.049	SF3B2
Regulation of PTEN stability and activity	1	61.4×	0.049	FRK
mRNA Splicing	1	36.6×	0.054	SF3B2
CHD1 and CHD2 subfamily	1	36.2×	0.054	SF3B2
mRNA Polyadenylation	1	29.3×	0.054	SF3B2
Processing of Capped Intron-Containing Pre-mRNA	1	27.4×	0.054	SF3B2
mRNA Splicing - Major Pathway	1	18.2×	0.072	SF3B2
Dengue Virus-Host Interactions	1	15.2×	0.077	SF3B2
Metabolism of RNA	1	13.9×	0.077	SF3B2
Neutrophil degranulation	1	7.7×	0.124	FRK

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
otic placode development	1	1404.3×	0.015	FOXI3
epidermal cell fate specification	1	561.7×	0.015	FOXI3
fatty acid omega-oxidation	1	468.1×	0.015	CYP4V2
parathyroid gland development	1	401.2×	0.015	FOXI3
DNA replication-dependent chromatin assembly	1	351.1×	0.015	CHAF1A
sterol metabolic process	1	140.4×	0.025	CYP4V2
pharyngeal system development	1	133.8×	0.025	FOXI3
protein quality control for misfolded or incompletely synthesized proteins	1	127.7×	0.025	ZYG11B
U2-type prespliceosome assembly	1	104.0×	0.028	SF3B2
retinoid metabolic process	1	82.6×	0.031	CYP4V2
hair follicle development	1	63.8×	0.035	FOXI3
cell differentiation	2	9.7×	0.035	FOXI3, FRK
thymus development	1	56.2×	0.035	FOXI3
odontogenesis of dentin-containing tooth	1	50.1×	0.037	FOXI3
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	1	35.1×	0.049	ZYG11B
cell surface receptor protein tyrosine kinase signaling pathway	1	29.0×	0.055	FRK
DNA replication	1	27.5×	0.055	CHAF1A
nucleosome assembly	1	23.4×	0.058	CHAF1A
anatomical structure morphogenesis	1	23.2×	0.058	FOXI3
mRNA splicing, via spliceosome	1	15.3×	0.082	SF3B2
RNA splicing	1	14.7×	0.082	SF3B2
visual perception	1	13.2×	0.083	CYP4V2
mRNA processing	1	13.1×	0.083	SF3B2
DNA repair	1	10.6×	0.098	CHAF1A
negative regulation of transcription by RNA polymerase II	1	3.0×	0.306	FRK
regulation of transcription by RNA polymerase II	1	1.9×	0.416	FOXI3

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 6 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
FRK	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FRK	71	4
SF3B2	1	2
CHAF1A	0	0
CYP4V2	0	0
ZYG11B	0	0
FOXI3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FRK
AFATINIB	4	FRK
FEDRATINIB	4	FRK
TIVOZANIB	4	FRK
SORAFENIB	4	FRK
DASATINIB ANHYDROUS	4	FRK
IBRUTINIB	4	FRK
ENTRECTINIB	4	FRK
DABRAFENIB	4	FRK
CABOZANTINIB	4	FRK
PEMETREXED	4	FRK
VANDETANIB	4	FRK
NILOTINIB	4	FRK
BOSUTINIB	4	FRK
LORLATINIB	4	FRK
TOVORAFENIB	4	FRK
BRIGATINIB	4	FRK
ZANUBRUTINIB	4	FRK
PAZOPANIB	4	FRK
NINTEDANIB	4	FRK
SUNITINIB	4	FRK
DASATINIB	4	FRK
ERLOTINIB	4	FRK
QUIZARTINIB	4	FRK
CRIZOTINIB	4	FRK
MIDOSTAURIN	4	FRK
GEFITINIB	4	FRK
IMATINIB	4	FRK
VATALANIB	3	FRK
MASITINIB	3	FRK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
FRK	271	Binding:269, Functional:1, ADMET:1
SF3B2	20	Binding:20
ZYG11B	12	Binding:12

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP4V2	1.14.14.79	docosahexaenoic acid omega-hydroxylase
FRK	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
FRK	271

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
PONATINIB	4	FRK
AFATINIB	4	FRK
FEDRATINIB	4	FRK
TIVOZANIB	4	FRK
SORAFENIB	4	FRK
DASATINIB ANHYDROUS	4	FRK
IBRUTINIB	4	FRK
ENTRECTINIB	4	FRK
DABRAFENIB	4	FRK
CABOZANTINIB	4	FRK
PEMETREXED	4	FRK
VANDETANIB	4	FRK
NILOTINIB	4	FRK
BOSUTINIB	4	FRK
LORLATINIB	4	FRK
TOVORAFENIB	4	FRK
BRIGATINIB	4	FRK
ZANUBRUTINIB	4	FRK
PAZOPANIB	4	FRK
NINTEDANIB	4	FRK
SUNITINIB	4	FRK
DASATINIB	4	FRK
ERLOTINIB	4	FRK
QUIZARTINIB	4	FRK
CRIZOTINIB	4	FRK
MIDOSTAURIN	4	FRK
GEFITINIB	4	FRK
IMATINIB	4	FRK
VATALANIB	3	FRK
MASITINIB	3	FRK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FRK
B	Phased (≥1) drug, not yet approved	1	SF3B2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CYP4V2
E	Difficult family or no structure, no drug	3	CHAF1A, ZYG11B, FOXI3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CHAF1A	0	—
CYP4V2	0	—
ZYG11B	12	—
FOXI3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.