ZFYVE28

Chr 4

zinc finger FYVE-type containing 28

Also known as: LST2, LYST2, lst-2

NCBI Gene: 57732 ENSG00000159733 UniProt: Q9HCC9 OMIM: 614176

The protein binds phosphatidylinositol-3-phosphate and negatively regulates epidermal growth factor receptor signaling by promoting receptor degradation in endosomes. Mutations cause spastic tetraplegia with thin corpus callosum and progressive microcephaly, inherited in an autosomal recessive pattern. This gene is highly constrained against loss-of-function variants, suggesting that complete loss of protein function is poorly tolerated.

OMIM ResearchSummary from RefSeq, UniProt

Enables phosphatidylinositol-3-phosphate binding activity. Involved in negative regulation of epidermal growth factor-activated receptor activity. Located in cytosol and early endosome membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.46

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.46LOEUF

pLI 0.072

Z-score 4.01

OE 0.26 (0.16–0.46)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.25Z-score

OE missense 1.03 (0.96–1.10)

608 obs / 590.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.26 (0.16–0.46)

0≤0.351.4

Missense OE?1.03 (0.96–1.10)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 9 / 34.4Missense obs/exp: 608 / 590.9Syn Z: -1.57

Background carrier burden — how many people carry a rare variant somewhere in ZFYVE28?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 27

1,468 rare PASS variants

Rare truncating (LoF)

1 in 2,100

109 rare PASS variants

Rare synonymous (reference)

1 in 33

689 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ZFYVE28. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 39	1 in 2,200
South Asian	~43k	1 in 26	≈ 1 in 11,000
Remaining (unassigned)	~30k	1 in 29	1 in 1,900
European (Finnish)	~27k	1 in 110	1 in 1,800
Admixed American	~22k	1 in 27	1 in 2,000
African / African American	~21k	1 in 31	1 in 1,700
East Asian	~20k	1 in 31	1 in 2,700
Ashkenazi Jewish	~13k	1 in 170	≈ 1 in 4,600
Middle Eastern	~2,884	1 in 28	≈ 1 in 950

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 11 of 13 coding exons well covered in gnomAD exomes; exons 1, 2 marginal. Genomes: all 13.? see exons ↓