FIG4

Chr 6ARAD

FIG4 phosphoinositide 5-phosphatase

Also known as: ALS11, BOP, BTOP, CMT4J, KIAA0274, SAC3, YVS, dJ249I4.1

NCBI Gene: 9896ENSG00000112367UniProt: Q92562

The protein encoded by this gene belongs to the SAC domain-containing protein gene family. The SAC domain, approximately 400 amino acids in length and consisting of seven conserved motifs, has been shown to possess phosphoinositide phosphatase activity. The yeast homolog, Sac1p, is involved in the regulation of various phosphoinositides, and affects diverse cellular functions such as actin cytoskeleton organization, Golgi function, and maintenance of vacuole morphology. Membrane-bound phosphoinositides function as signaling molecules and play a key role in vesicle trafficking in eukaryotic cells. Mutations in this gene have been associated with Charcot-Marie-Tooth disease, type 4J. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

?Polymicrogyria, bilateral temporooccipitalMIM #612691
AR
Amyotrophic lateral sclerosis 11MIM #612577
AD
Charcot-Marie-Tooth disease, type 4JMIM #611228
AR
Yunis-Varon syndromeMIM #216340
AR
1203
ClinVar variants
61
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— FIG4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
61 Pathogenic / Likely Pathogenic· 184 VUS of 1203 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
1.24LOEUF
pLI 0.000
Z-score 0.10
OE 0.98 (0.79–1.24)
Tolerant

Highly tolerant — LoF variants common in population

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.
1.88Z-score
OE missense 0.76 (0.70–0.83)
381 obs / 498.9 exp
Tolerant

Mild missense constraint

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.0.98 (0.79–1.24)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.70–0.83)
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.1.04
0≤1.21.6
LoF obs/exp: 52 / 52.8Missense obs/exp: 381 / 498.9Syn Z: -0.46

ClinVar Variant Classifications

1203 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31
Likely Pathogenic30
VUS184
Likely Benign222
Benign9
Conflicting2
31
Pathogenic
30
Likely Pathogenic
184
VUS
222
Likely Benign
9
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
2
17
0
31
Likely Pathogenic
22
1
7
0
30
VUS
2
154
27
1
184
Likely Benign
0
1
118
103
222
Benign
0
0
9
0
9
Conflicting
—2
Total36158178104478

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

View in ClinVar →

Protein Context — Lollipop Plot

FIG4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

FIG4-related cleidocranial dysplasia with micrognathia, absent thumbs, and distal aphalangia (Yunis-Varon syndrome)

strong
ARLoss 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

?Polymicrogyria, bilateral temporooccipital

MIM #612691

Molecular basis of disorder known

Autosomal recessive

Amyotrophic lateral sclerosis 11

MIM #612577

Molecular basis of disorder known

Autosomal dominant

Charcot-Marie-Tooth disease, type 4J

MIM #611228

Molecular basis of disorder known

Autosomal recessive

Yunis-Varon syndrome

MIM #216340

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons.
Shi Y et al.·Nat Med
2018
The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy.
Deneubourg C et al.·Autophagy
2022
FIG4-Related Parkinsonism and the Particularities of the I41T Mutation: A Review of the Literature.
Boura I et al.·Genes (Basel)
2024Review
Fig4 deficiency: a newly emerged lysosomal storage disorder?
Martyn C et al.·Prog Neurobiol
2013Review
Clinical Characteristics of Charcot-Marie-Tooth Disease Type 4J.
Sadjadi R et al.·Neurology
2024
A Role of Inflammation in Charcot-Marie-Tooth Disorders-In a Perspective of Treatment?
Kamińska J et al.·Int J Mol Sci
2024Review
Biallelic loss-of-function variants of SLC12A9 cause lysosome dysfunction and a syndromic neurodevelopmental disorder.
Accogli A et al.·Genet Med
2024
Genetic epidemiology of amyotrophic lateral sclerosis in Cyprus: a population-based study.
Mitsi E et al.·Sci Rep
2024
Clinical and radiological characterization of novel FIG4-related combined system disease with neuropathy.
Wright GC et al.·Clin Genet
2020
Cerebral hypomyelination associated with biallelic variants of FIG4.
Lenk GM et al.·Hum Mutat
2019
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
Charcot-Marie-Tooth Disease Type 4J

Study of Intrathecal ELP-02 for Charcot-Marie-Tooth Disease Type 4J (CMT4J)

NOT YET RECRUITING
NCT07447557Phase PHASE1, PHASE2Elpida Therapeutics SPCStarted 2026-04
ELP-02

External Resources

Links to major genomics databases and tools