Is ERCC8 p.Asp266Ala (c.797A>C) pathogenic?

ERCC8 p.Asp266Ala (c.797A>C) is classified Likely pathogenic in ERCC8 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9947); Very rare (popmax 0.00167%, amr); Associated with Cockayne syndrome type 1.

What condition is associated with ERCC8 p.Asp266Ala (c.797A>C)?

ERCC8 p.Asp266Ala (c.797A>C) is associated with Cockayne syndrome type 1 (ClinVar).

How common is ERCC8 p.Asp266Ala (c.797A>C) in the general population?

ERCC8 p.Asp266Ala (c.797A>C) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Cockayne syndrome inherited?

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

What do computational predictors say about ERCC8 p.Asp266Ala (c.797A>C)?

AlphaMissense predicts likely pathogenic (score 0.9947) — an in-silico prediction, not a clinical call.

ERCC8 p.Asp266Ala

c.797A>C · rs281875225 · VCV973767

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cockayne syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.9947	likely pathogenic ✓ concordant with ClinVar · top 3% in ERCC8
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -15.33	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.89 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 1.2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 70 kb · p 0.027 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,014 alleles

Overall 6.84e-05% 1/1,461,390 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.Asp266Ala
Coding: c.797A>C
MANE Select: NM_000082
dbSNP: rs281875225
Type: single nucleotide variant
Location: chr5:60898322 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 16 PDB
Residue 266: a UniProt-annotated variant site (in csa); a turn

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.Asp266Gly Pathogenic/Likely pathogenic ★★ same residue
ERCC8 p.Asp266= Likely benign ★ same residue
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
ERCC8 c.276-1G>A 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-asp266ala (accessed [today's date]).

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