Is ERCC2 p.Lys692fs (c.2068_2069dup) pathogenic?

ERCC2 p.Lys692fs (c.20682069dup) is classified Pathogenic/Likely pathogenic in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-28). Very rare (popmax 8.47e-05%, nfe); Associated with cerebrooculofacioskeletal syndrome 2.

What condition is associated with ERCC2 p.Lys692fs (c.2068_2069dup)?

ERCC2 p.Lys692fs (c.2068_2069dup) is associated with cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Lys692fs (c.2068_2069dup) in the general population?

ERCC2 p.Lys692fs (c.2068_2069dup) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

ERCC2 p.Lys692fs

c.2068_2069dup · rs2513998080 · VCV3241395

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 8.47e-05%, nfe)

Conditions

cerebrooculofacioskeletal syndrome 2

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 22 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -6.1	GERP -3.1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 6.84e-05% 1/1,461,766 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.Lys692fs
Coding: c.2068_2069dup
MANE Select: NM_000400
dbSNP: rs2513998080
Type: Duplication
Location: chr19:45352329 (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 692: an α-helix

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

Disease context

cerebrooculofacioskeletal syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERCC2 c.1377+1dup Likely pathogenic ★★ same condition
ERCC2 c.1479+2dup Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Ala600fs Likely pathogenic ★★ same condition
ERCC2 p.Ile432fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Leu337fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Phe720fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Tyr625fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Val623fs 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/ercc2-p-lys692fs (accessed [today's date]).

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