Is ERCC5 p.Pro223= (c.669A>C) pathogenic?

ERCC5 p.Pro223= (c.669A>C) is classified Uncertain significance in ERCC5 (ClinVar, Single submitter, 2 submitters; last evaluated 2018-01-13). Ultra-rare (popmax 0.0395%, sas); Associated with xeroderma pigmentosum group G.

What condition is associated with ERCC5 p.Pro223= (c.669A>C)?

ERCC5 p.Pro223= (c.669A>C) is associated with xeroderma pigmentosum group G (ClinVar).

How common is ERCC5 p.Pro223= (c.669A>C) in the general population?

ERCC5 p.Pro223= (c.669A>C) is ultra-rare (popmax 0.0395%, sas) (gnomAD).

ERCC5 p.Pro223=

Q: How is Xeroderma pigmentosum-Cockayne syndrome complex inherited?

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

c.669A>C · rs541094745 · VCV310915

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, sas)

Conditions

xeroderma pigmentosum group G

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.46	GERP -0.19, phastCons 0.82
Overall
CADD	7.526	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0395% South Asian · 36/91,088 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.00254% 41/1,614,174 alleles · ultra-rare exomes 38/1,461,816 · genomes 3/152,358 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0395%	2,530
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)	0.000254%	393,334

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: ERCC5
Protein: p.Pro223=
Coding: c.669A>C
MANE Select: NM_000123
dbSNP: rs541094745
Type: single nucleotide variant
Location: chr13:102858415 (GRCh38)

Full ERCC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

xeroderma pigmentosum group G — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

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/ercc5-p-pro223 (accessed [today's date]).

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