Is FIG4 p.Arg899Ter (c.2695C>T) pathogenic?

FIG4 p.Arg899Ter (c.2695C>T) is classified Uncertain significance in FIG4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-05-20). Ultra-rare (popmax 0.0329%, mid); Associated with Charcot-Marie-Tooth disease type 4J.

What condition is associated with FIG4 p.Arg899Ter (c.2695C>T)?

FIG4 p.Arg899Ter (c.2695C>T) is associated with Charcot-Marie-Tooth disease type 4J, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Arg899Ter (c.2695C>T) in the general population?

FIG4 p.Arg899Ter (c.2695C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

How is Charcot-Marie-Tooth disease type 4J inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

FIG4 p.Arg899Ter

c.2695C>T · rs750069994 · VCV476864

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

Charcot-Marie-Tooth disease type 4J

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (23 of 23) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 1.2, phastCons 1
Overall
CADD	38.0	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 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.0013% 21/1,613,874 alleles · ultra-rare exomes 20/1,461,774 · genomes 1/152,100 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
East Asian	0.00223%	44,864
Admixed American	0.00167%	59,996
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)	0.00136%	73,747

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.Arg899Ter
Coding: c.2695C>T
MANE Select: NM_014845
dbSNP: rs750069994
Type: single nucleotide variant
Location: chr6:109825236 (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 4J — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Charcot-Marie-Tooth disease type 4J (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult, Childhood, Infancy

Similar variants

FIG4 p.Arg899Gln 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-arg899ter (accessed [today's date]).

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