Is ERCC2 c.5+6A>C pathogenic?

ERCC2 c.5+6A>C is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-11). Ultra-rare (popmax 0.0381%, eas); Associated with xeroderma pigmentosum group D.

What condition is associated with ERCC2 c.5+6A>C?

ERCC2 c.5+6A>C is associated with xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 c.5+6A>C in the general population?

ERCC2 c.5+6A>C is ultra-rare (popmax 0.0381%, eas) (gnomAD).

ERCC2 c.5+6A>C

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

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

rs751637822 · VCV329532

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0381%, eas)

Conditions

xeroderma pigmentosum group D

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +6	donor splice region (+6, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.8	GERP -3.6
Non-coding constraint	Z 1.16	1 kb window · o/e 0.92 · regional · uncalibrated
Overall
CADD	7.828	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0381% East Asian · 16/41,958 alleles

Filtering AF 0.0239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0195%

Overall 0.00141% 20/1,415,330 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0381%	2,622
European (non-Finnish)	0.000346%	289,380

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: ERCC2
Coding: c.5+6A>C
MANE Select: NM_000400
dbSNP: rs751637822
Type: single nucleotide variant
Location: chr19:45370530 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB

Full ERCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1480-2A>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1666-2A>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1759-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.183+2T>A Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.361-1G>A Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.816-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Ala717Gly 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/ercc2-c-5-plus-6a-c (accessed [today's date]).

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