FIG4

Chr 6ARAD

FIG4 phosphoinositide 5-phosphatase

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

NCBI Gene: 9896 ENSG00000112367 UniProt: Q92562 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

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

131 unique Pathogenic / Likely Pathogenic· 462 VUS of 1162 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 →

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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 OE?0.98 (0.79–1.24)

0≤0.351.4

Missense OE?0.76 (0.70–0.83)

0≤0.61.4

Synonymous OE?1.04

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

This gene — mechanism propensity

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

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.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 24004519 ↗

ClinVar Variant Classifications

1162 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic75

Likely Pathogenic56

VUS462

Likely Benign434

Benign69

Conflicting44

Pathogenic

Likely Pathogenic

462

VUS

434

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	63	4	8	0	75
Likely Pathogenic	49	4	3	0	56
VUS	11	396	48	7	462
Likely Benign	0	4	230	200	434
Benign	0	1	67	1	69
Conflicting	—				44
Total	123	409	356	208	1,140

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap FIG4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →