NAFLD1

Summary

NAFLD1 (MONDO:0021105) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 81

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	NAFLD1
Mondo ID	MONDO:0021105
OMIM	613282
UMLS	C2750440
MedGen	413307
Is cancer (heuristic)	no

Also known as: fatty liver disease, nonalcoholic, susceptibility to, 1 · liver disease, alcoholic, susceptibility to, 1 · NAFLD1

Data availability: 81 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › liver disorder › fatty liver disease › metabolic dysfunction-associated steatotic liver disease › NAFLD1

Related subtypes (1): metabolic dysfunction-associated steatohepatitis

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

81 retrieved; paginated sample, class counts are floors:

48 uncertain significance, 15 likely benign, 12 benign, 3 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1677281	NM_001349232.2(ATG7):c.1277C>T (p.Pro426Leu)	ATG7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341932	NM_025225.3(PNPLA3):c.444C>G (p.Ile148Met)	PNPLA3	Conflicting classifications of pathogenicity; risk factor	criteria provided, conflicting classifications
341943	NM_025225.3(PNPLA3):c.1300A>G (p.Lys434Glu)	PNPLA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
902436	NM_025225.3(PNPLA3):c.1262C>T (p.Pro421Leu)	LOC121627950	Uncertain significance	criteria provided, multiple submitters, no conflicts
341924	NM_025225.3(PNPLA3):c.-44C>G	PNPLA3	Uncertain significance	criteria provided, single submitter
341931	NM_025225.3(PNPLA3):c.414C>T (p.Val138=)	PNPLA3	Uncertain significance	criteria provided, single submitter
341935	NM_025225.3(PNPLA3):c.646A>C (p.Thr216Pro)	PNPLA3	Uncertain significance	criteria provided, multiple submitters, no conflicts
341939	NM_025225.3(PNPLA3):c.980-14A>C	PNPLA3	Uncertain significance	criteria provided, single submitter
341942	NM_025225.3(PNPLA3):c.1209C>T (p.Pro403=)	PNPLA3	Uncertain significance	criteria provided, single submitter
341944	NM_025225.3(PNPLA3):c.1340G>A (p.Arg447Gln)	PNPLA3	Uncertain significance	criteria provided, single submitter
341947	NM_025225.3(PNPLA3):c.1419C>T (p.Pro473=)	PNPLA3	Uncertain significance	criteria provided, single submitter
341948	NM_025225.3(PNPLA3):c.*19T>G	PNPLA3	Uncertain significance	criteria provided, single submitter
341950	NM_025225.3(PNPLA3):c.*71T>G	PNPLA3	Uncertain significance	criteria provided, single submitter
341951	NM_025225.3(PNPLA3):c.*141T>G	PNPLA3	Uncertain significance	criteria provided, single submitter
341958	NM_025225.3(PNPLA3):c.*960T>G	PNPLA3	Uncertain significance	criteria provided, single submitter
341962	NM_025225.3(PNPLA3):c.*990T>A	PNPLA3	Uncertain significance	criteria provided, single submitter
341963	NM_025225.3(PNPLA3):c.*1068C>T	PNPLA3	Uncertain significance	criteria provided, single submitter
341964	NM_025225.3(PNPLA3):c.*1076C>T	PNPLA3	Uncertain significance	criteria provided, single submitter
341966	NM_025225.3(PNPLA3):c.*1175A>C	PNPLA3	Uncertain significance	criteria provided, single submitter
899623	NM_025225.3(PNPLA3):c.484G>A (p.Val162Met)	PNPLA3	Uncertain significance	criteria provided, multiple submitters, no conflicts
899624	NM_025225.3(PNPLA3):c.494T>C (p.Val165Ala)	PNPLA3	Uncertain significance	criteria provided, multiple submitters, no conflicts
899625	NM_025225.3(PNPLA3):c.557C>A (p.Pro186His)	PNPLA3	Uncertain significance	criteria provided, multiple submitters, no conflicts
899626	NM_025225.3(PNPLA3):c.599C>T (p.Thr200Met)	PNPLA3	Uncertain significance	criteria provided, single submitter
899627	NM_025225.3(PNPLA3):c.617A>C (p.Asp206Ala)	PNPLA3	Uncertain significance	criteria provided, single submitter
899690	NM_025225.3(PNPLA3):c.*176G>A	PNPLA3	Uncertain significance	criteria provided, single submitter
899691	NM_025225.3(PNPLA3):c.*222G>A	PNPLA3	Uncertain significance	criteria provided, single submitter
899693	NM_025225.3(PNPLA3):c.*346G>A	PNPLA3	Uncertain significance	criteria provided, single submitter
900686	NM_025225.2(PNPLA3):c.-180C>T	PNPLA3	Uncertain significance	criteria provided, single submitter
900687	NM_025225.2(PNPLA3):c.-131C>G	PNPLA3	Uncertain significance	criteria provided, single submitter
900688	NM_025225.2(PNPLA3):c.-108T>C	PNPLA3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATG7	HGNC:16935	ENSG00000197548	O95352	Ubiquitin-like modifier-activating enzyme ATG7	clinvar
PNPLA3	HGNC:18590	ENSG00000100344	Q9NST1	1-acylglycerol-3-phosphate O-acyltransferase PNPLA3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATG7	Ubiquitin-like modifier-activating enzyme ATG7	E1-like activating enzyme involved in the 2 ubiquitin-like systems required for cytoplasm to vacuole transport (Cvt) and autophagy.
PNPLA3	1-acylglycerol-3-phosphate O-acyltransferase PNPLA3	Specifically catalyzes coenzyme A (CoA)-dependent acylation of 1-acyl-sn-glycerol 3-phosphate (2-lysophosphatidic acid/LPA) to generate phosphatidic acid (PA), an important metabolic intermediate and precursor for both triglycerides and gl…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATG7	Other/Unknown	no		ThiF_NAD_FAD-bd, Atg7, Atg7_N
PNPLA3	Other/Unknown	no		PNPLA_dom, Acyl_Trfase/lysoPLipase, PLPL

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1
buccal mucosa cell	1
pigmented layer of retina	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATG7	232	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
PNPLA3	178	ubiquitous	marker	pigmented layer of retina, buccal mucosa cell, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATG7	5,169
PNPLA3	1,441

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATG7	O95352	88.06
PNPLA3	Q9NST1	71.70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 2 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
Acyl chain remodeling of DAG and TAG	1	815.7×	0.017	PNPLA3
Dengue Virus Attachment and Entry	1	129.8×	0.038	ATG7
Oncogenic MAPK signaling	1	124.1×	0.038	ATG7
Signaling by BRAF and RAF1 fusions	1	85.2×	0.038	ATG7
Autophagy	1	74.2×	0.038	ATG7
Macroautophagy	1	57.7×	0.040	ATG7
Class I MHC mediated antigen processing & presentation	1	35.0×	0.057	ATG7
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.061	ATG7
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.083	ATG7
Adaptive Immune System	1	14.9×	0.092	ATG7
Innate Immune System	1	12.8×	0.098	ATG7
Neutrophil degranulation	1	11.5×	0.099	ATG7
Disease	1	6.5×	0.148	ATG7
Immune System	1	6.5×	0.148	ATG7

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
triglyceride acyl-chain remodeling	1	8426.0×	0.002	PNPLA3
positive regulation of protein modification process	1	4213.0×	0.002	ATG7
cellular response to 3,3’,5-triiodo-L-thyronine	1	4213.0×	0.002	PNPLA3
protein modification by small protein conjugation	1	2808.7×	0.002	ATG7
acylglycerol acyl-chain remodeling	1	2106.5×	0.002	PNPLA3
protein lipidation	1	1685.2×	0.002	ATG7
response to sucrose	1	1685.2×	0.002	PNPLA3
cellular response to hyperoxia	1	1685.2×	0.002	ATG7
glycerophospholipid metabolic process	1	1404.3×	0.002	PNPLA3
cellular response to nitrogen starvation	1	766.0×	0.004	ATG7
lipid droplet organization	1	468.1×	0.005	PNPLA3
piecemeal microautophagy of the nucleus	1	468.1×	0.005	ATG7
cellular response to stress	1	421.3×	0.005	ATG7
white fat cell differentiation	1	421.3×	0.005	PNPLA3
triglyceride catabolic process	1	401.2×	0.005	PNPLA3
triglyceride biosynthetic process	1	366.4×	0.005	PNPLA3
long-chain fatty acid metabolic process	1	312.1×	0.006	PNPLA3
phosphatidic acid biosynthetic process	1	255.3×	0.007	PNPLA3
lipid homeostasis	1	168.5×	0.010	PNPLA3
mitophagy	1	159.0×	0.010	ATG7
regulation of circadian rhythm	1	129.6×	0.011	ATG7
rhythmic process	1	125.8×	0.011	ATG7
macroautophagy	1	120.4×	0.011	ATG7
autophagosome assembly	1	112.3×	0.011	ATG7
positive regulation of protein catabolic process	1	101.5×	0.012	ATG7
cellular response to starvation	1	96.8×	0.012	ATG7
cellular response to insulin stimulus	1	85.1×	0.013	PNPLA3
autophagy	1	55.1×	0.020	ATG7
defense response to virus	1	34.7×	0.031	ATG7
positive regulation of apoptotic process	1	28.4×	0.036	ATG7

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATG7	0	0
PNPLA3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ATG7	12	Binding:12

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	ATG7, PNPLA3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATG7	12	—
PNPLA3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.