Is GEN1 p.Lys188fs (c.562_563del) pathogenic?

GEN1 p.Lys188fs (c.562563del) is classified Uncertain significance in GEN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-10). Very rare (popmax 0.00223%, eas).

How common is GEN1 p.Lys188fs (c.562_563del) in the general population?

GEN1 p.Lys188fs (c.562_563del) is very rare (popmax 0.00223%, eas) (gnomAD).

GEN1 p.Lys188fs

c.562_563del · rs1416729020 · VCV2182248

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 0.00223%, 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 5 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.2	GERP 0.24, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,770 alleles

Overall 6.22e-05% 1/1,607,498 alleles · very rare exomes 1/1,455,218 · genomes 0/152,280 · 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: GEN1
Protein: p.Lys188fs
Coding: c.562_563del
MANE Select: NM_001130009
dbSNP: rs1416729020
Type: Deletion
Location: chr2:17766615 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 1 PDB
Residue 188: the 'xpg-i domain' region; an α-helix

Full GEN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GEN1 p.Lys188Arg Uncertain significance ★ ⚠ same residue
GEN1 p.Lys188= Likely benign ★ same residue
GEN1 p.Lys839fs Benign ★★ same type
GEN1 c.1072-7_1072-2del Uncertain significance ★ same type
GEN1 p.Arg115fs Uncertain significance ★ same type
GEN1 p.Arg59fs Uncertain significance ★ same type
GEN1 p.Asn539_Ala540del Uncertain significance ★ same type
GEN1 p.Asn571fs Uncertain significance ★ 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/gen1-p-lys188fs (accessed [today's date]).

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