Is FIG4 p.Arg867fs (c.2597dup) pathogenic?

FIG4 p.Arg867fs (c.2597dup) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). Very rare (popmax 0.000424%, nfe).

How common is FIG4 p.Arg867fs (c.2597dup) in the general population?

FIG4 p.Arg867fs (c.2597dup) is very rare (popmax 0.000424%, nfe) (gnomAD).

FIG4 p.Arg867fs

c.2597dup · VCV4893743

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	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 · substitutions only
Constraint at this position
Conservation	phyloP 5.1	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,884 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,613,924 alleles · very rare exomes 6/1,461,728 · genomes 0/152,196 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,010
European (non-Finnish)grpmax	0.000424%	235,977

Finnish 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.Arg867fs
Coding: c.2597dup
MANE Select: NM_014845
Type: Duplication
Location: chr6:109825133 (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

Similar variants

FIG4 p.Arg867Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
FIG4 p.Arg867Thr Uncertain significance ★ ⚠ same residue
FIG4 p.Glu767fs Pathogenic/Likely pathogenic ★★ same type
FIG4 p.Leu458fs Pathogenic ★★ same type
FIG4 p.Pro605fs Pathogenic ★★ same type
FIG4 p.Ser750fs Pathogenic ★★ same type
FIG4 p.Thr556fs Pathogenic/Likely pathogenic ★★ same type
FIG4 p.Thr689fs Pathogenic/Likely pathogenic ★★ same type

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-arg867fs (accessed [today's date]).

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