Is FIG4 p.Pro718= (c.2154A>G) pathogenic?

FIG4 p.Pro718= (c.2154A>G) is classified Conflicting classifications of pathogenicity in FIG4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0493%, mid); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Pro718= (c.2154A>G)?

FIG4 p.Pro718= (c.2154A>G) is associated with Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease (ClinVar).

How common is FIG4 p.Pro718= (c.2154A>G) in the general population?

FIG4 p.Pro718= (c.2154A>G) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

FIG4 p.Pro718=

c.2154A>G · rs201138266 · VCV476855

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.36	GERP -4.2, phastCons 0.72
Overall
CADD	6.604	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,080 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.0105% 169/1,613,270 alleles · ultra-rare exomes 162/1,461,016 · genomes 7/152,254 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,027
European (non-Finnish)	0.0131%	7,659
Remaining individualsnot grpmax-eligible	0.0128%	7,807
Admixed American	0.005%	20,001
African / African-American	0.00133%	74,936

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.Pro718=
Coding: c.2154A>G
MANE Select: NM_014845
dbSNP: rs201138266
Type: single nucleotide variant
Location: chr6:109789651 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 718: the 'disordered' region

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

Similar variants

FIG4 p.Pro718Ala Uncertain significance ★★ ⚠ same residue
FIG4 c.1040-1G>A Likely pathogenic ★★ same condition
FIG4 c.1584-1G>T Likely pathogenic ★★ same condition
FIG4 c.1948+1G>A Likely pathogenic ★★ same condition
FIG4 c.1949-10T>G Pathogenic/Likely pathogenic ★★ same condition
FIG4 c.2459+1G>A Pathogenic ★★ same condition
FIG4 c.877-2A>C Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Arg152Ter Pathogenic/Likely pathogenic ★★ 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-pro718 (accessed [today's date]).

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