Is FIG4 p.Lys657fs (c.1970_1973del) pathogenic?

FIG4 p.Lys657fs (c.19701973del) is classified Likely pathogenic in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-08). Very rare (popmax 0.00891%, eas).

How common is FIG4 p.Lys657fs (c.1970_1973del) in the general population?

FIG4 p.Lys657fs (c.1970_1973del) is very rare (popmax 0.00891%, eas) (gnomAD).

FIG4 p.Lys657fs

c.1970_1973del · rs1343672462 · VCV2440259

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.4	GERP 2.3, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,872 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000248% 4/1,613,082 alleles · very rare exomes 4/1,460,778 · genomes 0/152,304 · joint denominator

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.Lys657fs
Coding: c.1970_1973del
MANE Select: NM_014845
dbSNP: rs1343672462
Type: Deletion
Location: chr6:109786321 (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 c.1749_1750+7del Likely pathogenic ★★ same type
FIG4 c.1750+1del Pathogenic/Likely pathogenic ★★ same type
FIG4 p.Arg384fs Pathogenic/Likely pathogenic ★★ same type
FIG4 p.Lys278fs Pathogenic ★★ same type
FIG4 p.Phe254fs Pathogenic ★★ same type
FIG4 p.Tyr106fs Pathogenic/Likely pathogenic ★★ same type
FIG4 c.2377-10del Benign ★★ same type
FIG4 c.2377-11_2377-10del Benign/Likely benign ★★ 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-lys657fs (accessed [today's date]).

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