# NM_014845.6(FIG4):c.285T>A (p.Val95=)

https://sugi.bio/variant/fig4-p-val95

## Summary

**FIG4 p.Val95= (c.285T>A)** is classified **Likely benign** in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-09). Very rare (popmax 0.000424%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

**At a glance:** Likely benign · review: Single submitter · rsID rs1775437411 · 1 submitter · 1 linked condition · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the FIG4 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Charcot-Marie-Tooth disease type 4.

*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/0012440/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.Val95= |
| Coding change (HGVS c.) | c.285T>A |
| MANE Select transcript | [NM_014845](https://www.ncbi.nlm.nih.gov/nuccore/NM_014845) |
| dbSNP | [rs1775437411](https://www.ncbi.nlm.nih.gov/snp/rs1775437411/) |
| Variant type | single nucleotide variant |
| Location | chr6:109716564-109716564 (GRCh38) |
| ClinVar | [VCV3016223](https://www.ncbi.nlm.nih.gov/clinvar/variation/3016223/) |

**All HGVS expressions:** `LRG_241:g.30344T>A`, `LRG_241t1:c.285T>A`, `NC_000006.11:g.110037767T>A`, `NC_000006.12:g.109716564T>A`, `NG_007977.1:g.30344T>A`, `NM_014845.6:c.285T>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 -0.081, GERP -3.16, phastCons 0.868 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.933**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.72 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,179,772 in the highest group · 5/1,613,734 alleles overall — very rare (popmax 0.000424%, nfe).

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-09.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-03-09 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease type 4](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-4/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease, type IV, Charcot-Marie-Tooth, Type 4.

## Similar variants {#similar}

Related FIG4 variant pages (same residue, condition, or type): [FIG4 c.1040-1G>A](/variant/fig4-c-1040-minus-1g-a), [FIG4 c.1584-1G>T](/variant/fig4-c-1584-minus-1g-t), [FIG4 c.1948+1G>A](/variant/fig4-c-1948-plus-1g-a), [FIG4 c.1949-10T>G](/variant/fig4-c-1949-minus-10t-g), [FIG4 c.2459+1G>A](/variant/fig4-c-2459-plus-1g-a), [FIG4 c.877-2A>C](/variant/fig4-c-877-minus-2a-c), [FIG4 p.Arg152Ter](/variant/fig4-p-arg152ter), [FIG4 p.Arg183Ter](/variant/fig4-p-arg183ter).

### 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 3016223). 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.*