# NM_014845.6(FIG4):c.294del (p.Phe98fs)

https://sugi.bio/variant/fig4-p-phe98fs

## Summary

**FIG4 p.Phe98fs (c.294del)** is classified **Pathogenic** in FIG4 (ClinVar, Single submitter, 4 submitters; last evaluated 2019-10-02). Very rare (popmax 0.00167%, amr); Associated with Yunis-Varon syndrome.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1562648373 · 4 submitters · 3 linked conditions · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the FIG4 gene that is reported as disease-causing, but on limited review, submitted by 4 submitters, and is linked to Yunis-Varon syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000331/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FIG4](https://sugi.bio/atlas/gene/FIG4/) |
| Protein change (HGVS p.) | p.Phe98fs |
| Coding change (HGVS c.) | c.294del |
| MANE Select transcript | [NM_014845](https://www.ncbi.nlm.nih.gov/nuccore/NM_014845) |
| dbSNP | [rs1562648373](https://www.ncbi.nlm.nih.gov/snp/rs1562648373/) |
| Variant type | Deletion |
| Location | chr6:109727110-109727110 (GRCh38) |
| ClinVar | [VCV1722](https://www.ncbi.nlm.nih.gov/clinvar/variation/1722/) |

**All HGVS expressions:** `LRG_241:g.40893del`, `NC_000006.11:g.110048316del`, `NC_000006.12:g.109727113del`, `NG_007977.1:g.40893del`, `NM_014845.5:c.294delT`, `NM_014845.6:c.294del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 11.456, GERP 2.56, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.966, pLI 1.3237e-16. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 23**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/59,962 in the highest group · 1/1,607,916 alleles overall — very rare (popmax 0.00167%, amr).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**FIG4** population constraint: LOEUF 0.966, pLI 1.3237e-16, missense-Z 1.7961. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Charcot-Marie-Tooth disease** — Definitive (AR)
- **amyotrophic lateral sclerosis type 11** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.65, 50% of residues very-high.

**1 experimental structure(s)** (PDB): [7K1W](https://www.rcsb.org/structure/7K1W).

## What this gene does {#gene-function}

*Describes the biological roles of FIG4 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

FIG4 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of PIPs at the Golgi membrane](https://reactome.org/content/detail/R-HSA-1660514) | electronic |
| [Synthesis of PIPs at the early endosome membrane](https://reactome.org/content/detail/R-HSA-1660516) | electronic |
| [Synthesis of PIPs at the late endosome membrane](https://reactome.org/content/detail/R-HSA-1660517) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate metabolic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-10-02.

**Submitter consensus:** conflicting (2 Uncertain significance, 2 Pathogenic).

**Submission history:** 4 submissions (2007–2019); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Inherited Neuropathy Consortium | Uncertain significance | no assertion criteria provided | literature only |  |
| Inherited Neuropathy Consortium Ii, University Of Miami | Uncertain significance | no assertion criteria provided | literature only | 2016-01-06 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2007-07-05 |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Pathogenic | criteria provided, single submitter | clinical testing | 2019-10-02 |

## Associated conditions {#conditions}

[Yunis-Varon syndrome](https://sugi.bio/atlas/disease/yunis-varon-syndrome/), [Charcot-Marie-Tooth disease type 4J](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-4j/), [Charcot-Marie-Tooth disease](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease/).

**Reported phenotype names (ClinVar):** Yunis-Varon syndrome, Charcot-Marie-Tooth disease type 4J, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth Neuropathy, Charcot-Marie-Tooth Hereditary Neuropathy, Cleidocranial dysplasia, micrognathia, absent thumbs, & distal aphalangia, CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4J, Charcot-Marie-Tooth Neuropathy Type 4J, CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL RECESSIVE, TYPE 4J.

## Similar variants {#similar}

Related FIG4 variant pages (same residue, condition, or type): [FIG4 c.1750+1del](/variant/fig4-c-1750-plus-1del), [FIG4 p.Arg384fs](/variant/fig4-p-arg384fs), [FIG4 p.Lys278fs](/variant/fig4-p-lys278fs), [FIG4 p.Phe254fs](/variant/fig4-p-phe254fs), [FIG4 p.Asp348fs](/variant/fig4-p-asp348fs), [FIG4 p.Thr601fs](/variant/fig4-p-thr601fs), [FIG4 p.Thr422fs](/variant/fig4-p-thr422fs), [FIG4 c.1040-1G>A](/variant/fig4-c-1040-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1722). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*