Is ERCC8 p.Ala219Pro (c.655G>C) pathogenic?

ERCC8 p.Ala219Pro (c.655G>C) is classified Conflicting classifications of pathogenicity in ERCC8 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-21). AlphaMissense: likely pathogenic (0.6321); Rare (popmax 0.19%, nfe); Associated with UV-sensitive syndrome 2.

What condition is associated with ERCC8 p.Ala219Pro (c.655G>C)?

ERCC8 p.Ala219Pro (c.655G>C) is associated with UV-sensitive syndrome 2, Cockayne syndrome type 1 (ClinVar).

How common is ERCC8 p.Ala219Pro (c.655G>C) in the general population?

ERCC8 p.Ala219Pro (c.655G>C) is rare (popmax 0.19%, nfe) (gnomAD).

How is UV-sensitive syndrome inherited?

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

What do computational predictors say about ERCC8 p.Ala219Pro (c.655G>C)?

AlphaMissense predicts likely pathogenic (score 0.6321) — an in-silico prediction, not a clinical call.

ERCC8 p.Ala219Pro

c.655G>C · rs150727525 · VCV702384

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6321 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.19%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

UV-sensitive syndrome 2

Computational evidence

Protein change
AlphaMissense	0.6321	likely pathogenic
REVEL	0.679	pathogenic-leaning
SaProt	LLR -3.58	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 70 kb · p 0.027 · regional, not allelic
Overall
CADD	24.6	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 0.19% European (non-Finnish) · 2,242/1,178,878 alleles

Filtering AF 0.184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.181%

Overall 0.168% 2,712/1,612,304 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.52%	40
Finnishnot grpmax-eligible	0.515%	194
European (non-Finnish)grpmax	0.19%	526
Remaining individualsnot grpmax-eligible	0.13%	771
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,687
Middle Eastern	0.033%	3,028
African / African-American	0.0253%	3,947
Admixed American	0.01%	9,998

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala219Pro
Coding: c.655G>C
MANE Select: NM_000082
dbSNP: rs150727525
Type: single nucleotide variant
Location: chr5:60899690 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 16 PDB
Residue 219: a β-strand

Full ERCC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

UV-sensitive syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Cockayne syndrome type 1

For UV-sensitive syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

ERCC8 p.Ala219Val Uncertain significance ★ ⚠ same residue
ERCC8 p.Ala219= 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-ala219pro (accessed [today's date]).

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