Is FIG4 p.Arg265Ter (c.793C>T) pathogenic?

FIG4 p.Arg265Ter (c.793C>T) is classified Pathogenic/Likely pathogenic in FIG4 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-10-18). Ultra-rare (popmax 0.0165%, mid); Associated with Charcot-Marie-Tooth disease type 4J.

What condition is associated with FIG4 p.Arg265Ter (c.793C>T)?

FIG4 p.Arg265Ter (c.793C>T) is associated with Charcot-Marie-Tooth disease type 4J, Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Arg265Ter (c.793C>T) in the general population?

FIG4 p.Arg265Ter (c.793C>T) is ultra-rare (popmax 0.0165%, 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.Arg265Ter

c.793C>T · rs774294963 · VCV488991

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Charcot-Marie-Tooth disease type 4J

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 23
Splicing
SpliceAI	Δ0.50	acceptor loss, 17 bp away · masked 0 · deltas
Pangolin	Δ0.43	loss · gain 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1	GERP 0.2, phastCons 0.44
Overall
CADD	39.0	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 0.0165% Middle Eastern · 1/6,074 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000931% 15/1,611,928 alleles · ultra-rare exomes 6/1,459,820 · genomes 9/152,108 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.879%	114
Middle Easterngrpmax	0.0165%	6,074
South Asian	0.00329%	30,359
Admixed American	0.00167%	59,946
European (non-Finnish)	0.00017%	589,154

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg265Ter
Coding: c.793C>T
MANE Select: NM_014845
dbSNP: rs774294963
Type: single nucleotide variant
Location: chr6:109741461 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 265: the sac domain

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 type 4

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

Inheritance: Autosomal recessive
Onset: Adult, Childhood, Infancy

Similar variants

FIG4 p.Arg265Gln Uncertain significance ★★ ⚠ same residue
FIG4 p.Arg265= Likely benign ★ 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

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-arg265ter (accessed [today's date]).

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