Is ERCC2 p.Arg669fs (c.2005_2006del) pathogenic?

ERCC2 p.Arg669fs (c.20052006del) is classified Pathogenic/Likely pathogenic in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-05). Very rare (popmax 0.0033%, nfe); Associated with cerebrooculofacioskeletal syndrome 2.

What condition is associated with ERCC2 p.Arg669fs (c.2005_2006del)?

ERCC2 p.Arg669fs (c.2005_2006del) is associated with cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Arg669fs (c.2005_2006del) in the general population?

ERCC2 p.Arg669fs (c.2005_2006del) is very rare (popmax 0.0033%, nfe) (gnomAD).

ERCC2 p.Arg669fs

c.2005_2006del · rs757535186 · VCV2675050

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 0.0033%, 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 21 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.53	GERP -0.002, phastCons 0.022
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0033% European (non-Finnish) · 39/1,180,042 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.0026% 42/1,614,034 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0033%	30,257
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-American	0.00133%	74,934

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.Arg669fs
Coding: c.2005_2006del
MANE Select: NM_000400
dbSNP: rs757535186
Type: Deletion
Location: chr19:45352546 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB

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.106-5_142del Likely pathogenic ★★ same condition
ERCC2 c.1347_1377+7del Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.2047-13_2048del Likely pathogenic ★★ same condition
ERCC2 c.2190+1del Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.594+2_594+5del Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Arg196_Tyr197insTer Pathogenic ★★ same condition
ERCC2 p.Gln662fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Gly622fs 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-arg669fs (accessed [today's date]).

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