Cholestasis, progressive familial intrahepatic, 8

disease

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Also known as PFIC8

Summary

Cholestasis, progressive familial intrahepatic, 8 (MONDO:0030505) is a disease caused by KIF12 (GenCC Strong), with 1 cohort gene.

At a glance

Causal gene: KIF12 (GenCC Strong)
Cohort genes: 1
ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cholestasis, progressive familial intrahepatic, 8
Mondo ID	MONDO:0030505
OMIM	619662
UMLS	C5562045
MedGen	1794255
GARD	0025584
Is cancer (heuristic)	no

Also known as: PFIC8

Data availability: 15 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › progressive familial intrahepatic cholestasis › cholestasis, progressive familial intrahepatic, 8

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

15 retrieved; paginated sample, class counts are floors:

8 likely pathogenic, 5 uncertain significance, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1328486	NM_001388308.1(KIF12):c.1069C>T (p.Arg357Ter)	KIF12	Pathogenic	no assertion criteria provided
1328488	NM_001388308.1(KIF12):c.877C>T (p.Arg293Ter)	KIF12	Pathogenic	criteria provided, multiple submitters, no conflicts
1328487	NM_001388308.1(KIF12):c.1024G>A (p.Val342Met)	KIF12	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705359	NM_001388308.1(KIF12):c.430del (p.Ala144fs)	KIF12	Likely pathogenic	criteria provided, single submitter
3064811	NM_001388308.1(KIF12):c.375+1G>T	KIF12	Likely pathogenic	criteria provided, single submitter
3064812	NM_001388308.1(KIF12):c.1723C>T (p.Arg575Ter)	KIF12	Likely pathogenic	criteria provided, single submitter
4279710	NM_001388308.1(KIF12):c.1103G>A (p.Arg368Gln)	KIF12	Likely pathogenic	no assertion criteria provided
4292894	NM_001388308.1(KIF12):c.1623_1624insCC (p.Arg542fs)	KIF12	Likely pathogenic	criteria provided, single submitter
4293689	NM_001388308.1(KIF12):c.92+2T>C	KIF12	Likely pathogenic	criteria provided, single submitter
4819688	NM_001388308.1(KIF12):c.896dup	KIF12	Likely pathogenic	criteria provided, single submitter
1328489	NM_001388308.1(KIF12):c.1070G>A (p.Arg357Gln)	KIF12	Uncertain significance	criteria provided, single submitter
2065343	NM_001388308.1(KIF12):c.1900del (p.Gln634fs)	KIF12	Uncertain significance	criteria provided, multiple submitters, no conflicts
2501777	NM_001388308.1(KIF12):c.704A>G (p.His235Arg)	KIF12	Uncertain significance	criteria provided, single submitter
3779794	NM_001388308.1(KIF12):c.1102C>T (p.Arg368Ter)	KIF12	Uncertain significance	criteria provided, single submitter
4293418	NM_001388308.1(KIF12):c.1075G>A (p.Ala359Thr)	KIF12	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
KIF12	Strong	Autosomal recessive	cholestasis, progressive familial intrahepatic, 8	3

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
KIF12	HGNC:21495	ENSG00000136883	Q96FN5	Kinesin-like protein KIF12	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIF12	Kinesin-like protein KIF12	Involved in the negative regulation of fatty acid biosynthesis, probably acting as an adapter that allows ubiquitination of acetyl-CoA carboxylase 1 (ACACA) by E3 ubiquitin-protein ligase COP1, and promotes ACACA degradation.

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)
KIF12	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase

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
adult mammalian kidney	1
body of pancreas	1
metanephros cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIF12	165	broad	marker	metanephros cortex, body of pancreas, adult mammalian kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIF12	916

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KIF12	Q96FN5	71.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Kinesins	1	178.4×	0.009	KIF12
COPI-dependent Golgi-to-ER retrograde traffic	1	110.9×	0.009	KIF12

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of fatty acid biosynthetic process	1	887.0×	0.003	KIF12
microtubule-based movement	1	295.6×	0.005	KIF12
ubiquitin-dependent protein catabolic process	1	74.2×	0.013	KIF12

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KIF12	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KIF12

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KIF12	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: KIF12