IFAP syndrome 2

Summary

IFAP syndrome 2 (MONDO:0100221) is a disease caused by SREBF1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SREBF1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	IFAP syndrome 2
Mondo ID	MONDO:0100221
OMIM	619016
UMLS	C5436607
MedGen	1763502
GARD	0016402
Is cancer (heuristic)	no

Also known as: ichthyosis , follicular, with atrichia and photophobia syndrome 2 · ichthyosis follicularis, atrichia, and photophobia syndrome 2 · IFAP SYNDROME 2 · IFAP2

Data availability: 11 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › IFAP syndrome › IFAP syndrome 2

Related subtypes (1): IFAP syndrome 1, with or without BRESHECK 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

11 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 3 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
932243	NM_004176.5(SREBF1):c.1579C>T (p.Arg527Cys)	SREBF1	Pathogenic	criteria provided, multiple submitters, no conflicts
932244	NM_004176.5(SREBF1):c.1582_1584del (p.Asn528del)	SREBF1	Pathogenic	no assertion criteria provided
932245	NM_004176.5(SREBF1):c.1589T>C (p.Leu530Pro)	SREBF1	Pathogenic	no assertion criteria provided
2456472	NM_004176.5(SREBF1):c.457G>A (p.Ala153Thr)	SREBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2363509	NM_004176.5(SREBF1):c.835G>A (p.Gly279Arg)	SREBF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892556	NM_004176.5(SREBF1):c.1122A>C (p.Gln374His)	SREBF1	Uncertain significance	criteria provided, single submitter
3892557	NM_004176.5(SREBF1):c.265G>A (p.Gly89Arg)	SREBF1	Uncertain significance	criteria provided, single submitter
3892558	NM_004176.5(SREBF1):c.2717G>A (p.Arg906Gln)	SREBF1	Uncertain significance	criteria provided, single submitter
3892560	NM_004176.5(SREBF1):c.3322C>T (p.Arg1108Cys)	SREBF1	Uncertain significance	criteria provided, single submitter
3892561	NM_004176.5(SREBF1):c.41C>A (p.Ala14Glu)	SREBF1	Uncertain significance	criteria provided, single submitter
3892562	NM_004176.5(SREBF1):c.991A>G (p.Ile331Val)	SREBF1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
SREBF1	Strong	Autosomal dominant	IFAP syndrome 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SREBF1	Orphanet:388	Hirschsprung disease

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
SREBF1	HGNC:11289	ENSG00000072310	P36956	Sterol regulatory element-binding protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SREBF1	Sterol regulatory element-binding protein 1	Precursor of the transcription factor form (Processed sterol regulatory element-binding protein 1), which is embedded in the endoplasmic reticulum membrane.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SREBF1	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf

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
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SREBF1	172	ubiquitous	marker	left adrenal gland, right adrenal gland, left adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SREBF1	4,089

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SREBF1	P36956	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
Zymostenol biosynthesis via lathosterol (Kandutsch-Russell pathway)	1	1268.9×	0.005	SREBF1
Cholesterol biosynthesis	1	1142.0×	0.005	SREBF1
NR1H2 & NR1H3 regulate gene expression linked to lipogenesis	1	1142.0×	0.005	SREBF1
R-HSA-1368082	1	713.8×	0.006	SREBF1
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	1	407.9×	0.006	SREBF1
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	380.7×	0.006	SREBF1
R-HSA-400253	1	346.1×	0.006	SREBF1
FOXO-mediated transcription	1	335.9×	0.006	SREBF1
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	317.2×	0.006	SREBF1
Activation of gene expression by SREBF (SREBP)	1	259.6×	0.007	SREBF1
Metabolism of steroids	1	137.6×	0.012	SREBF1
Transcriptional regulation of white adipocyte differentiation	1	129.8×	0.012	SREBF1
PPARA activates gene expression	1	94.4×	0.015	SREBF1
Metabolism of lipids	1	31.6×	0.041	SREBF1
RNA Polymerase II Transcription	1	22.5×	0.053	SREBF1
Gene expression (Transcription)	1	17.8×	0.063	SREBF1
Generic Transcription Pathway	1	15.1×	0.070	SREBF1
Metabolism	1	11.6×	0.086	SREBF1

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
regulation of heart rate by chemical signal	1	5617.3×	0.003	SREBF1
negative regulation of triglyceride metabolic process	1	4213.0×	0.003	SREBF1
response to fructose	1	2407.4×	0.003	SREBF1
obsolete regulation of protein targeting to mitochondrion	1	2106.5×	0.003	SREBF1
regulation of fatty acid metabolic process	1	1872.4×	0.003	SREBF1
SREBP signaling pathway	1	1872.4×	0.003	SREBF1
response to glucagon	1	1685.2×	0.003	SREBF1
positive regulation of triglyceride biosynthetic process	1	1296.3×	0.003	SREBF1
regulation of mitophagy	1	1203.7×	0.003	SREBF1
positive regulation of cholesterol biosynthetic process	1	1123.5×	0.003	SREBF1
lipid biosynthetic process	1	991.3×	0.003	SREBF1
cellular response to fatty acid	1	702.2×	0.004	SREBF1
response to cAMP	1	510.7×	0.004	SREBF1
response to food	1	495.6×	0.004	SREBF1
response to progesterone	1	495.6×	0.004	SREBF1
negative regulation of insulin secretion	1	495.6×	0.004	SREBF1
insulin secretion	1	432.1×	0.005	SREBF1
cholesterol biosynthetic process	1	421.3×	0.005	SREBF1
response to retinoic acid	1	383.0×	0.005	SREBF1
mRNA transcription by RNA polymerase II	1	330.4×	0.005	SREBF1
response to nutrient	1	295.6×	0.005	SREBF1
positive regulation of miRNA transcription	1	290.6×	0.005	SREBF1
response to glucose	1	255.3×	0.006	SREBF1
circadian rhythm	1	244.2×	0.006	SREBF1
insulin receptor signaling pathway	1	221.7×	0.006	SREBF1
lung development	1	198.3×	0.007	SREBF1
cellular response to starvation	1	193.7×	0.007	SREBF1
fat cell differentiation	1	181.2×	0.007	SREBF1
response to ethanol	1	146.5×	0.008	SREBF1
regulation of protein stability	1	125.8×	0.009	SREBF1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

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
SREBF1	CALCIFEDIOL ANHYDROUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SREBF1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CALCIFEDIOL ANHYDROUS	4	SREBF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SREBF1	17	Binding:17

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)
CALCIFEDIOL ANHYDROUS	4	SREBF1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SREBF1
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	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.