ZFYVE9

Chr 1

zinc finger FYVE-type containing 9

Also known as: MADHIP, NSP, PPP1R173, SARA, SMADIP

NCBI Gene: 9372ENSG00000157077UniProt: O95405OMIM: 603755

This gene encodes an early endosomal protein that recruits SMAD2 and SMAD3 to intracellular membranes and the TGF-beta receptor, regulating their subcellular localization and modulating SMAD3/SMAD4 transcriptional activity in TGF-beta signaling pathways. The gene is highly constrained against loss-of-function variants (pLI 0.90, LOEUF 0.33), suggesting mutations likely cause autosomal dominant disease, though specific associated phenotypes are not yet established in clinical databases.

OMIMResearchSummary from RefSeq, UniProt
LOFmechanismLOEUF 0.33
Clinical Summary— ZFYVE9
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.90). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
7 unique Pathogenic / Likely Pathogenic· 171 VUS of 215 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.33LOEUF
pLI 0.902
Z-score 5.57
OE 0.20 (0.12–0.33)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
1.80Z-score
OE missense 0.81 (0.76–0.87)
604 obs / 741.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.20 (0.12–0.33)
0≤0.351.4
Missense OE0.81 (0.76–0.87)
0≤0.61.4
Synonymous OE0.93
0≤1.21.6
LoF obs/exp: 11 / 56.0Missense obs/exp: 604 / 741.8Syn Z: 0.85
DN
0.3594th %ile
GOF
0.4085th %ile
LOF
0.73top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.33

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

215 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic2
VUS171
Likely Benign11
5
Pathogenic
2
Likely Pathogenic
171
VUS
11
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
5
0
5
Likely Pathogenic
0
0
2
0
2
VUS
0
166
5
0
171
Likely Benign
0
9
0
2
11
Benign
0
0
0
0
0
Total0175122189

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ZFYVE9 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Genome-wide single nucleotide polymorphism (SNP) data reveal potential candidate genes for litter traits in a Yorkshire pig population
Zhang Y et al.·Arch Anim Breed
2023
Epigenome-Wide Changes in the Cell Layers of the Vein Wall When Exposing the Venous Endothelium to Oscillatory Shear Stress
Smetanina MA et al.·Epigenomes
2023
Whole genome sequencing identifies rare germline variants enriched in cancer related genes in first degree relatives of familial pancreatic cancer patients
Tan M et al.·Clin Genet
2021Cohort
Identification of Potential Signatures and Their Functions for Acute Lymphoblastic Leukemia: A Study Based on the Cancer Genome Atlas
Wang W et al.·Front Genet
2021
Comprehensive Analysis of the Expression of TGF-beta Signaling Regulators and Prognosis in Human Esophageal Cancer
Song W et al.·Comput Math Methods Med
2021
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 2 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC

No open access results found

Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients