Is FIG4 p.Phe254fs (c.759del) pathogenic?

FIG4 p.Phe254fs (c.759del) is classified Pathogenic in FIG4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-09-17). Ultra-rare (popmax 0.0178%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Phe254fs (c.759del)?

FIG4 p.Phe254fs (c.759del) is associated with Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 4J, amyotrophic lateral sclerosis type 11 (ClinVar).

How common is FIG4 p.Phe254fs (c.759del) in the general population?

FIG4 p.Phe254fs (c.759del) is ultra-rare (popmax 0.0178%, nfe) (gnomAD).

FIG4 p.Phe254fs

c.759del · rs764717219 · VCV254668

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, 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 7 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.83	GERP -1.5, phastCons 0.016
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 0.0178% European (non-Finnish) · 210/1,179,096 alleles

Filtering AF 0.0158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.0131% 212/1,612,684 alleles · ultra-rare exomes 210/1,460,546 · genomes 2/152,138 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0178%	5,615
Remaining individualsnot grpmax-eligible	0.00321%	31,194

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.Phe254fs
Coding: c.759del
MANE Select: NM_014845
dbSNP: rs764717219
Type: Deletion
Location: chr6:109738435 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 254: the sac domain

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 amyotrophic lateral sclerosis type 11 Charcot-Marie-Tooth disease

Similar variants

FIG4 p.Phe254= Likely benign ★★ same residue
FIG4 p.Phe254Leu Uncertain significance ★ ⚠ same residue
FIG4 c.1749_1750+7del Likely pathogenic ★★ same condition
FIG4 c.1750+1del Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Arg384fs Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Lys278fs Pathogenic ★★ same condition
FIG4 p.Tyr106fs Pathogenic/Likely pathogenic ★★ same condition
FIG4 c.2377-10del 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-phe254fs (accessed [today's date]).

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