Is ERCC2 p.Leu52= (c.156G>A) pathogenic?

ERCC2 p.Leu52= (c.156G>A) is classified Conflicting classifications of pathogenicity in ERCC2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-28). Very rare (popmax 0.00127%, nfe); Associated with xeroderma pigmentosum.

What condition is associated with ERCC2 p.Leu52= (c.156G>A)?

ERCC2 p.Leu52= (c.156G>A) is associated with xeroderma pigmentosum, xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 p.Leu52= (c.156G>A) in the general population?

ERCC2 p.Leu52= (c.156G>A) is very rare (popmax 0.00127%, nfe) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

ERCC2 p.Leu52=

c.156G>A · rs202156896 · VCV754097

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

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 -2.4	GERP -2.4
Overall
CADD	7.895	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00127% European (non-Finnish) · 15/1,180,018 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00737% 119/1,614,040 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.301%	333
Remaining individualsnot grpmax-eligible	0.024%	4,166
European (non-Finnish)grpmax	0.00127%	78,668

Ashkenazi Jewish 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: ERCC2
Protein: p.Leu52=
Coding: c.156G>A
MANE Select: NM_000400
dbSNP: rs202156896
Type: single nucleotide variant
Location: chr19:45369097 (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 52: the helicase atp-binding domain; an α-helix

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

Also linked: xeroderma pigmentosum group D

For Xeroderma pigmentosum (Orphanet):

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

Similar variants

ERCC2 p.Leu52Pro Uncertain significance ★ ⚠ same residue
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

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-leu52 (accessed [today's date]).

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