Is ERCC8 p.Arg217fs (c.650del) pathogenic?

ERCC8 p.Arg217fs (c.650del) is classified Pathogenic/Likely pathogenic in ERCC8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-22). Ultra-rare (popmax 0.0165%, mid); Associated with Cockayne syndrome type 1.

What condition is associated with ERCC8 p.Arg217fs (c.650del)?

ERCC8 p.Arg217fs (c.650del) is associated with Cockayne syndrome type 1 (ClinVar).

How common is ERCC8 p.Arg217fs (c.650del) in the general population?

ERCC8 p.Arg217fs (c.650del) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Cockayne syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ERCC8 p.Arg217fs

c.650del · rs1561502158 · VCV640063

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Cockayne syndrome type 1

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 8 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.11	GERP 0.7, phastCons 0.56

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,054 alleles

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

Overall 0.000274% 4/1,460,230 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,054
Remaining individualsnot grpmax-eligible	0.0016%	62,442
European (non-Finnish)	0.00017%	589,438

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: ERCC8
Protein: p.Arg217fs
Coding: c.650del
MANE Select: NM_000082
dbSNP: rs1561502158
Type: Deletion
Location: chr5:60899695 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 16 PDB

Full ERCC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cockayne syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cockayne syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ERCC8 p.Asn75fs Pathogenic ★★ same condition
ERCC8 p.Glu55fs Pathogenic/Likely pathogenic ★★ same condition
ERCC8 p.Thr143fs Pathogenic/Likely pathogenic ★★ same condition
ERCC8 p.Trp127fs Pathogenic/Likely pathogenic ★★ same condition
ERCC8 p.Ala191del Likely pathogenic ★ same condition
ERCC8 p.Asn47fs Pathogenic ★ same condition
ERCC8 p.Asp199_Tyr200insTer Pathogenic ★ same condition
ERCC8 p.Asp227fs 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/ercc8-p-arg217fs (accessed [today's date]).

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