ANKFY1

Chr 17

ankyrin repeat and FYVE domain containing 1

Also known as: ANKHZN, BTBD23, ZFYVE14

NCBI Gene: 51479 ENSG00000185722 UniProt: Q9P2R3

This protein regulates endosomal trafficking and fusion, serving as an effector of Rab5 and binding phosphatidylinositol 3-phosphate to control vesicle transport between early endosomes, the Golgi, and lysosomes. Mutations cause autosomal dominant neurodevelopmental disorder with impaired intellectual development, hypotonia, and behavioral abnormalities. The gene is highly constrained against loss-of-function mutations, indicating that ANKFY1 haploinsufficiency is likely not tolerated in the general population.

ResearchSummary from RefSeq, UniProt

This gene encodes a cytoplasmic protein that contains a coiled-coil structure and a BTB/POZ domain at its N-terminus, ankyrin repeats in the middle portion, and a FYVE-finger motif at its C-terminus. This protein belongs to a subgroup of double zinc finger proteins which may be involved in vesicle or protein transport. Alternate splicing results in multiple transcript variants of this gene. [provided by RefSeq, Apr 2012]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.31

Clinical Summary— ANKFY1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

157 VUS of 255 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.956

Z-score 5.74

OE 0.19 (0.12–0.31)

Highly constrained

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

Missense Constraint?

2.46Z-score

OE missense 0.74 (0.69–0.80)

531 obs / 716.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.12–0.31)

0≤0.351.4

Missense OE?0.74 (0.69–0.80)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 11 / 58.3Missense obs/exp: 531 / 716.6Syn Z: 1.02

This gene — mechanism propensity

0.3495th %ile

GOF

0.5268th %ile

LOF

0.64top 25%

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

LOFprediction above median · LOEUF 0.31

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

255 submitted variants in ClinVar

ClinVar

Classification Summary

VUS157

Likely Benign38

Benign37

157

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	157	0	0	157
Likely Benign	7	8	23	38
Benign	1	31	5	37
Total	165	39	28	232

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 52) ClinVar copy-number / structural variants overlap ANKFY1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →