Is ERCC2 p.Ile569fs (c.1707del) pathogenic?

ERCC2 p.Ile569fs (c.1707del) is classified Pathogenic/Likely pathogenic in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-20). Very rare (popmax 0.000169%, nfe).

How common is ERCC2 p.Ile569fs (c.1707del) in the general population?

ERCC2 p.Ile569fs (c.1707del) is very rare (popmax 0.000169%, nfe) (gnomAD).

ERCC2 p.Ile569fs

c.1707del · rs767672172 · VCV1013170

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, 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	predicted	premature termination codon in exon 18 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,980 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,832 alleles · very rare

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: ERCC2
Protein: p.Ile569fs
Coding: c.1707del
MANE Select: NM_000400
dbSNP: rs767672172
Type: Deletion
Location: chr19:45353293 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 569: a β-strand; the 'mediates interaction with mms19' region

Full ERCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERCC2 p.Ile569Ser Uncertain significance ★★ ⚠ same residue
ERCC2 p.Ile569Met Uncertain significance ★ ⚠ same residue
ERCC2 p.Ile569Thr Uncertain significance ★ ⚠ same residue
MAG p.Glu569Lys Uncertain significance ★ ⚠ same residue
ERCC2 c.106-5_142del Likely pathogenic ★★ same type
ERCC2 c.1347_1377+7del Pathogenic/Likely pathogenic ★★ same type
ERCC2 c.2047-13_2048del Likely pathogenic ★★ same type
ERCC2 c.2190+1del 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/ercc2-p-ile569fs (accessed [today's date]).

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