Is ERCC2 p.Leu652del (c.1954_1956del) pathogenic?

ERCC2 p.Leu652del (c.19541956del) is classified Conflicting classifications of pathogenicity in ERCC2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-06-21). Very rare (popmax 0.005%, amr); Associated with trichothiodystrophy 1, photosensitive.

What condition is associated with ERCC2 p.Leu652del (c.1954_1956del)?

ERCC2 p.Leu652del (c.1954_1956del) is associated with trichothiodystrophy 1, photosensitive (ClinVar).

How common is ERCC2 p.Leu652del (c.1954_1956del) in the general population?

ERCC2 p.Leu652del (c.1954_1956del) is very rare (popmax 0.005%, amr) (gnomAD).

ERCC2 p.Leu652del

c.1954_1956del · rs775486463 · VCV2413346

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

trichothiodystrophy 1, photosensitive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 1.5, phastCons 1

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,006 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000616% 9/1,461,730 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,002
European (non-Finnish)	0.000508%	196,667

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.Leu652del
Coding: c.1954_1956del
MANE Select: NM_000400
dbSNP: rs775486463
Type: Deletion
Location: chr19:45352596 (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 652: an α-helix

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

Disease context

trichothiodystrophy 1, photosensitive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERCC2 c.2047-13_2048del Likely pathogenic ★★ same condition
ERCC2 c.594+2_594+5del Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Gln662fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Phe568fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Val714fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Leu652= Likely benign ★★ same residue
ERCC2 p.Asp673fs Likely pathogenic ★ same condition
ERCC2 p.Ser140fs 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-leu652del (accessed [today's date]).

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