# NM_014845.6(FIG4):c.2052C>T (p.Ser684=)

https://sugi.bio/variant/fig4-p-ser684

## Summary

**FIG4 p.Ser684= (c.2052C>T)** is classified **Conflicting classifications of pathogenicity** in FIG4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-11). Ultra-rare (popmax 0.0267%, amr); Associated with Charcot-Marie-Tooth disease type 4.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs183958565 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0267%, amr)

## For patients & families {#patients}

This is a change in the FIG4 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, 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.Ser684= |
| Coding change (HGVS c.) | c.2052C>T |
| MANE Select transcript | [NM_014845](https://www.ncbi.nlm.nih.gov/nuccore/NM_014845) |
| dbSNP | [rs183958565](https://www.ncbi.nlm.nih.gov/snp/rs183958565/) |
| Variant type | single nucleotide variant |
| Location | chr6:109786405-109786405 (GRCh38) |
| ClinVar | [VCV1102314](https://www.ncbi.nlm.nih.gov/clinvar/variation/1102314/) |

**All HGVS expressions:** `LRG_241:g.100185C>T`, `NC_000006.11:g.110107608C>T`, `NC_000006.12:g.109786405C>T`, `NG_007977.1:g.100185C>T`, `NM_014845.5:c.2052C>T`, `NM_014845.6:c.2052C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.46) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -2.742, GERP -4.56 — fast-evolving / accelerated position
- CADD: **PHRED 14.41**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.12**, acceptor gain **0.00**, donor gain **0.46**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.12**, acceptor gain **0.00**, donor gain **0.46**.
- Population frequency (gnomAD v4.1): grpmax **0.0267%** (amr) · FAF95 0.0166% · FAF99 0.0136% · 16/60,018 in the highest group · 24/1,613,952 alleles overall — ultra-rare (popmax 0.0267%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0267% | 3,751 |
| African / African-American | 0.008% | 12,506 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,247 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-11.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2025–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-29 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-02-11 |

## 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, not specified, not provided, Charcot-Marie-Tooth disease, type IV, Charcot-Marie-Tooth, Type 4, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related FIG4 variant pages (same residue, condition, or type): [FIG4 p.Ser684Arg](/variant/fig4-p-ser684arg), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1102314). 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.*