ZFYVE9

Chr 1

zinc finger FYVE-type containing 9

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

NCBI Gene: 9372 ENSG00000157077 UniProt: O95405 OMIM: 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.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a double zinc finger motif-containing protein that participates in the transforming growth factor-beta (TGFB) signalling pathway. The encoded protein interacts directly with SMAD2 and SMAD3, and recruits SMAD2 to the TGFB receptor. There are multiple pseudogenes for this gene on chromosomes 2, 15, and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.33

Clinical Summary— ZFYVE9

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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.

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ClinVar Variants

166 VUS of 203 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 OE?0.20 (0.12–0.33)

0≤0.351.4

Missense OE?0.81 (0.76–0.87)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 11 / 56.0Missense obs/exp: 604 / 741.8Syn Z: 0.85

This gene — mechanism propensity

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

203 submitted variants in ClinVar

ClinVar

Classification Summary

VUS166

Likely Benign11

166

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	166	0	166
Likely Benign	9	2	11
Benign	0	0	0
Total	175	2	177

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap ZFYVE9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →