FIG4

Chr 6ARAD

FIG4 phosphoinositide 5-phosphatase

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

NCBI Gene: 9896ENSG00000112367UniProt: Q92562OMIM: 609390

The protein is a phosphoinositide phosphatase that regulates membrane-bound signaling molecules essential for vesicle trafficking, actin cytoskeleton organization, and organelle morphology. Mutations cause autosomal recessive Charcot-Marie-Tooth disease type 4J, Yunis-Varon syndrome, bilateral temporooccipital polymicrogyria, and autosomal dominant amyotrophic lateral sclerosis 11. Loss of phosphatase activity disrupts endosomal membrane dynamics and cellular trafficking pathways.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismAR/ADLOEUF 1.244 OMIM phenotypes
Clinical Summary— FIG4
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Gene-Disease Validity (ClinGen)
amyotrophic lateral sclerosis type 11 · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
68 unique Pathogenic / Likely Pathogenic· 178 VUS of 500 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — FIG4
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
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
1.88Z-score
OE missense 0.76 (0.70–0.83)
381 obs / 498.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.98 (0.79–1.24)
0≤0.351.4
Missense OE0.76 (0.70–0.83)
0≤0.61.4
Synonymous OE1.04
0≤1.21.6
LoF obs/exp: 52 / 52.8Missense obs/exp: 381 / 498.9Syn Z: -0.46
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongFIG4-related cleidocranial dysplasia with micrognathia, absent thumbs, and distal aphalangia (Yunis-Varon syndrome)LOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.4686th %ile
GOF
0.4283th %ile
LOF
0.49top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

LOFOn the basis of the ability of reduced FIG4 levels to rescue aspects of Mtmr2-dependent neuropathy, we evaluated the effect of Fig4 haploinsufficiency on the myopathy of Mtm1-knockout mice.PMID:24004519

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

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic31
VUS178
Likely Benign221
Benign9
Conflicting2
37
Pathogenic
31
Likely Pathogenic
178
VUS
221
Likely Benign
9
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
27
3
7
0
37
Likely Pathogenic
26
3
2
0
31
VUS
3
149
23
3
178
Likely Benign
0
1
117
103
221
Benign
0
0
9
0
9
Conflicting
—2
Total56156158106478

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.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients