Is ERCC2 p.Ala139= (c.417C>G) pathogenic?

ERCC2 p.Ala139= (c.417C>G) is classified Benign/Likely benign in ERCC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-26). Rare (popmax 0.905%, afr); Associated with xeroderma pigmentosum.

What condition is associated with ERCC2 p.Ala139= (c.417C>G)?

ERCC2 p.Ala139= (c.417C>G) is associated with xeroderma pigmentosum (ClinVar).

How common is ERCC2 p.Ala139= (c.417C>G) in the general population?

ERCC2 p.Ala139= (c.417C>G) is rare (popmax 0.905%, afr) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

ERCC2 p.Ala139=

c.417C>G · rs145239390 · VCV695613

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.905%, afr)

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.33, phastCons 1
Overall
CADD	8.659	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.905% African / African-American · 679/75,048 alleles

Filtering AF 0.848% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.826%

Overall 0.0484% 782/1,614,194 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.905%	111
Remaining individualsnot grpmax-eligible	0.0752%	1,330
Admixed American	0.065%	1,539
Middle Eastern	0.0495%	2,021
European (non-Finnish)	0.00119%	84,288

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
Protein: p.Ala139=
Coding: c.417C>G
MANE Select: NM_000400
dbSNP: rs145239390
Type: single nucleotide variant
Location: chr19:45365102 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 139: the helicase atp-binding domain

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

Disease context

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

For Xeroderma pigmentosum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

ERCC2 p.Ala139Val Uncertain significance ★ ⚠ same residue
ERCC2 c.816-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Ala717Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
ERCC2 p.Ala725Pro Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Arg511Gln Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Arg601Leu Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Arg616Pro Pathogenic ★★ same condition
ERCC2 p.Arg616Trp 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-p-ala139 (accessed [today's date]).

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