Is FIG4 p.Arg381Ter (c.1141C>T) pathogenic?

FIG4 p.Arg381Ter (c.1141C>T) is classified Pathogenic in FIG4 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-11-18). Ultra-rare (popmax 0.016%, afr); Associated with Inborn genetic diseases.

What condition is associated with FIG4 p.Arg381Ter (c.1141C>T)?

FIG4 p.Arg381Ter (c.1141C>T) is associated with Inborn genetic diseases, Yunis-Varon syndrome, Charcot-Marie-Tooth disease type 4J (ClinVar).

How common is FIG4 p.Arg381Ter (c.1141C>T) in the general population?

FIG4 p.Arg381Ter (c.1141C>T) is ultra-rare (popmax 0.016%, afr) (gnomAD).

FIG4 p.Arg381Ter

c.1141C>T · rs377357931 · VCV217228

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Conditions

Inborn genetic diseases

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 11 of 23
Splicing
SpliceAI	Δ0.33	acceptor loss, 3 bp away · masked 0 · deltas
Pangolin	Δ0.49	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.97	GERP -4, phastCons 0.66
Overall
CADD	37.0	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 0.016% African / African-American · 12/74,978 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00721%

Overall 0.00217% 35/1,612,802 alleles · ultra-rare exomes 23/1,460,650 · genomes 12/152,152 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,248
Remaining individualsnot grpmax-eligible	0.0048%	20,817
European (non-Finnish)	0.00161%	62,051
South Asian	0.0011%	91,036

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.Arg381Ter
Coding: c.1141C>T
MANE Select: NM_014845
dbSNP: rs377357931
Type: single nucleotide variant
Location: chr6:109760253 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 381: the sac domain

Full FIG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Yunis-Varon syndrome Charcot-Marie-Tooth disease type 4J Charcot-Marie-Tooth disease type 4

Similar variants

FIG4 p.Arg381= 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.2376+2T>G 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-arg381ter (accessed [today's date]).

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