Is FIG4 p.Phe686fs (c.2058del) pathogenic?

FIG4 p.Phe686fs (c.2058del) is classified Pathogenic in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-12). Very rare (popmax 8.48e-05%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Phe686fs (c.2058del)?

FIG4 p.Phe686fs (c.2058del) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Phe686fs (c.2058del) in the general population?

FIG4 p.Phe686fs (c.2058del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

FIG4 p.Phe686fs

c.2058del · VCV3632599

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.33	GERP -4.6, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,872 alleles

Overall 6.2e-05% 1/1,613,814 alleles · very rare exomes 0/1,461,690 · genomes 1/152,124 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FIG4
Protein: p.Phe686fs
Coding: c.2058del
MANE Select: NM_014845
Type: Deletion
Location: chr6:109786409 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB

Full FIG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FIG4 c.1749_1750+7del Likely pathogenic ★★ same condition
FIG4 c.1750+1del Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Lys278fs Pathogenic ★★ same condition
FIG4 p.Phe254fs Pathogenic ★★ same condition
FIG4 p.Tyr106fs Pathogenic/Likely pathogenic ★★ same condition
FIG4 c.2377-10del Benign ★★ same condition
FIG4 c.2377-11_2377-10del Benign/Likely benign ★★ same condition
FIG4 c.447-3del Benign/Likely benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/fig4-p-phe686fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown