FGD1

Chr XXLR

FYVE, RhoGEF and PH domain containing 1

Also known as: AAS, FGDY, MRXS16, ZFYVE3

NCBI Gene: 2245ENSG00000102302UniProt: P98174

This gene encodes a protein that contains Dbl (DH) and pleckstrin (PH) homology domains and is similar to the Rho family of small GTP-binding proteins. The encoded protein specifically binds to the Rho family GTPase Cdc42Hs and can stimulate the GDP-GTP exchange of the isoprenylated form of Cdc42Hs. It also stimulates the mitogen activated protein kinase cascade leading to c-Jun kinase SAPK/JNK1 activation. Defects in this gene are the cause of the faciogenital dysplasia in Aarskog-Scott syndrome and a syndromatic form of X-linked cognitive disability. [provided by RefSeq, Jul 2017]

Primary Disease Associations & Inheritance

Aarskog-Scott syndromeMIM #305400
XLR
444
ClinVar variants
121
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— FGD1
🧬
Gene-Disease Validity (ClinGen)
Aarskog-Scott syndrome, X-linked · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
121 Pathogenic / Likely Pathogenic· 173 VUS of 444 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.20LOEUF
pLI 1.000
Z-score 4.92
OE 0.06 (0.03–0.20)
Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.52Z-score
OE missense 0.52 (0.46–0.58)
215 obs / 417.2 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.03–0.20)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.52 (0.46–0.58)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 2 / 32.0Missense obs/exp: 215 / 417.2Syn Z: 0.35

ClinVar Variant Classifications

444 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic88
Likely Pathogenic33
VUS173
Likely Benign108
Benign30
Conflicting12
88
Pathogenic
33
Likely Pathogenic
173
VUS
108
Likely Benign
30
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
21
2
65
0
88
Likely Pathogenic
17
5
11
0
33
VUS
4
140
23
6
173
Likely Benign
0
22
35
51
108
Benign
0
2
17
11
30
Conflicting
—12
Total4217115168444

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

View in ClinVar →

Protein Context — Lollipop Plot

FGD1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

FGD1-related Aarskog-Scott syndrome

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Aarskog-Scott syndrome

MIM #305400

Molecular basis of disorder known

X-linked recessive
📖
GeneReview available — FGD1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Aarskog-Scott syndrome: a clinical study based on a large series of 111 male patients with a pathogenic variant in FGD1 and management recommendations.
Jeanne M et al.·J Med Genet
2025Cohort
Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid.
Kadura S et al.·J Antimicrob Chemother
2020Review
FGD1-related Aarskog-Scott syndrome: Identification of four novel variations and a literature review of clinical and molecular aspects.
Li S et al.·Eur J Pediatr
2024Review
Delamanid Resistance: Update and Clinical Management.
Nguyen TVA et al.·Clin Infect Dis
2020Review
Lumbar ribs: a comprehensive review.
Aly I et al.·Childs Nerv Syst
2016Review
FGD1 promotes tumor progression and regulates tumor immune response in osteosarcoma via inhibiting PTEN activity.
Wu W et al.·Theranostics
2020
Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene.
Orrico A et al.·Am J Med Genet A
2010
Aarskog-scott syndrome (AAS): a case report.
Braiotta F et al.·Eur J Paediatr Dent
2023Case report
Xp11.22 duplications in four unrelated Chinese families: delineating the genotype-phenotype relationship for HSD17B10 and FGD1.
Wang Q et al.·BMC Med Genomics
2020Case report
Silencing FYVE, RhoGEF, and PH domain containing 1 (FGD1) suppresses melanoma progression by inhibiting PI3K/AKT signaling pathway.
Niu Z et al.·Bioengineered
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools