Is ERCC8 p.Val168= (c.504A>G) pathogenic?

ERCC8 p.Val168= (c.504A>G) is classified Benign/Likely benign in ERCC8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-30). Low-frequency (popmax 1.96%, afr); Associated with Cockayne syndrome type 1.

What condition is associated with ERCC8 p.Val168= (c.504A>G)?

ERCC8 p.Val168= (c.504A>G) is associated with Cockayne syndrome type 1 (ClinVar).

How common is ERCC8 p.Val168= (c.504A>G) in the general population?

ERCC8 p.Val168= (c.504A>G) is low-frequency (popmax 1.96%, afr) (gnomAD).

How is Cockayne syndrome inherited?

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

ERCC8 p.Val168=

c.504A>G · rs35366433 · VCV701917

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.96%, afr)

Conditions

Cockayne syndrome type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.1	GERP 1.9, phastCons 1
Overall
CADD	10.84	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.96% African / African-American · 1,473/75,000 alleles

Filtering AF 1.88% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.85%

Overall 0.104% 1,677/1,612,736 alleles · low-frequency exomes 792/1,460,590 · genomes 885/152,146 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.96%	51
Admixed American	0.15%	666
Remaining individualsnot grpmax-eligible	0.146%	686
Middle Eastern	0.103%	966
South Asian	0.00659%	15,172
European (non-Finnish)	0.000933%	107,204

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.Val168=
Coding: c.504A>G
MANE Select: NM_000082
dbSNP: rs35366433
Type: single nucleotide variant
Location: chr5:60903694 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 16 PDB
Residue 168: a β-strand

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.Val168Glu Uncertain significance ★ ⚠ 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
ERCC8 c.399+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-val168 (accessed [today's date]).

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