Is ERCC6 p.Lys478fs (c.1431_1432del) pathogenic?

ERCC6 p.Lys478fs (c.14311432del) is classified Pathogenic in ERCC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-17). Very rare (popmax 0.000339%, nfe); Associated with Cockayne syndrome.

What condition is associated with ERCC6 p.Lys478fs (c.1431_1432del)?

ERCC6 p.Lys478fs (c.1431_1432del) is associated with Cockayne syndrome (ClinVar).

How common is ERCC6 p.Lys478fs (c.1431_1432del) in the general population?

ERCC6 p.Lys478fs (c.1431_1432del) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Cockayne syndrome inherited?

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

ERCC6 p.Lys478fs

c.1431_1432del · rs746616255 · VCV1455192

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

Cockayne syndrome

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 6 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.5	GERP -0.44, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,582 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,196 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: ERCC6
Protein: p.Lys478fs
Coding: c.1431_1432del
MANE Select: NM_000124
dbSNP: rs746616255
Type: Microsatellite
Location: chr10:49505978 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 478: the 'n-terminal domain; essential for its chromatin remodeling activity' region

Full ERCC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cockayne syndrome — 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

PGBD3 p.Arg478His Uncertain significance ★ ⚠ same residue
ERCC6 c.1526+1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC6 c.2169+1G>A Likely pathogenic ★★ same condition
ERCC6 c.2287-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC6 c.2599-26A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC6 p.Arg1318fs Pathogenic/Likely pathogenic ★★ same condition
ERCC6 p.Arg176Ter Pathogenic ★★ same condition
ERCC6 p.Arg652Ter 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/ercc6-p-lys478fs (accessed [today's date]).

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