Is ERCC8 p.Leu281fs (c.840_841del) pathogenic?

ERCC8 p.Leu281fs (c.840841del) is classified Pathogenic in ERCC8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-01). Very rare (popmax 0.000657%); Associated with Cockayne syndrome type 1.

What condition is associated with ERCC8 p.Leu281fs (c.840_841del)?

ERCC8 p.Leu281fs (c.840_841del) is associated with Cockayne syndrome type 1 (ClinVar).

How common is ERCC8 p.Leu281fs (c.840_841del) in the general population?

ERCC8 p.Leu281fs (c.840_841del) is very rare (popmax 0.000657%) (gnomAD).

How is Cockayne syndrome inherited?

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

ERCC8 p.Leu281fs

c.840_841del · VCV3711413

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000657%)

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 9 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.3	GERP 1.2, phastCons 1
Overall
CADD	27.2	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 0.000657%

Overall 0.000657% 1/152,192 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: ERCC8
Protein: p.Leu281fs
Coding: c.840_841del
MANE Select: NM_000082
Type: Microsatellite
Location: chr5:60898278 (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.Leu124fs Pathogenic ★ same condition
ERCC8 p.Thr154fs Likely pathogenic ★ same condition
ERCC8 p.Glu395del Uncertain significance same condition
ERCC8 c.1041+1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC8 c.1042-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC8 c.173+1119G>C Pathogenic/Likely pathogenic ★★ same condition
ERCC8 c.173+1G>A Pathogenic/Likely pathogenic ★★ same condition
ERCC8 c.275+1G>A 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-leu281fs (accessed [today's date]).

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