Is FIG4 p.Lys663fs (c.1986dup) pathogenic?

FIG4 p.Lys663fs (c.1986dup) is classified Pathogenic in FIG4 (ClinVar, Single submitter, 3 submitters; last evaluated 2020-09-21). Very rare (popmax 0.00017%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Lys663fs (c.1986dup)?

FIG4 p.Lys663fs (c.1986dup) is associated with Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 4J, Charcot-Marie-Tooth disease (ClinVar).

How common is FIG4 p.Lys663fs (c.1986dup) in the general population?

FIG4 p.Lys663fs (c.1986dup) is very rare (popmax 0.00017%, nfe) (gnomAD).

FIG4 p.Lys663fs

c.1986dup · rs1197741113 · VCV637086

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, 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 8.2	GERP 1.2, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,482 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,222 alleles · very rare

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.Lys663fs
Coding: c.1986dup
MANE Select: NM_014845
dbSNP: rs1197741113
Type: Duplication
Location: chr6:109786338 (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

Also linked: Charcot-Marie-Tooth disease type 4J Charcot-Marie-Tooth disease

Similar variants

FIG4 p.Glu767fs Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Leu458fs Pathogenic ★★ same condition
FIG4 p.Pro605fs Pathogenic ★★ same condition
FIG4 p.Ser750fs Pathogenic ★★ same condition
FIG4 p.Thr556fs Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Thr689fs Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Gln888fs Uncertain significance ★★ same condition
FIG4 c.1889+6_1889+11dup 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-lys663fs (accessed [today's date]).

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