Is ERCC8 p.Tyr366fs (c.1095dup) pathogenic?

ERCC8 p.Tyr366fs (c.1095dup) is classified Uncertain significance in ERCC8 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-11-21). Very rare (popmax 0.00267%, afr); Associated with Cockayne syndrome type 1.

What condition is associated with ERCC8 p.Tyr366fs (c.1095dup)?

ERCC8 p.Tyr366fs (c.1095dup) is associated with Cockayne syndrome type 1 (ClinVar).

How common is ERCC8 p.Tyr366fs (c.1095dup) in the general population?

ERCC8 p.Tyr366fs (c.1095dup) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Cockayne syndrome inherited?

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

ERCC8 p.Tyr366fs

c.1095dup · rs750622098 · VCV550008

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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	escapes	premature termination codon within the last 50 nt of the penultimate exon (11 of 12, 26 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.9	GERP -3.8, phastCons 0.16
Overall
CADD	23.1	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 0.00267% African / African-American · 2/74,938 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000372% 6/1,613,696 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,469
European (non-Finnish)	0.000339%	294,928

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.Tyr366fs
Coding: c.1095dup
MANE Select: NM_000082
dbSNP: rs750622098
Type: Duplication
Location: chr5:60887466 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 16 PDB
Residue 366: a UniProt-annotated variant site (in csa)

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.Cys157fs Pathogenic/Likely pathogenic ★★ same condition
ERCC8 p.Ile201fs Pathogenic ★★ same condition
ERCC8 p.Trp107Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC8 p.Arg218Ter Pathogenic ★ same condition
ERCC8 p.Arg92fs Likely pathogenic ★ same condition
ERCC8 p.Tyr366Cys Uncertain significance ★ ⚠ same residue
ERCC8 c.1041+1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC8 c.1042-2A>G 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/ercc8-p-tyr366fs (accessed [today's date]).

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