Is ERCC2 p.Trp342fs (c.1024del) pathogenic?

ERCC2 p.Trp342fs (c.1024del) is classified Likely pathogenic in ERCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-27). Very rare (popmax 0.00273%, afr); Associated with cerebrooculofacioskeletal syndrome 2.

What condition is associated with ERCC2 p.Trp342fs (c.1024del)?

ERCC2 p.Trp342fs (c.1024del) is associated with cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Trp342fs (c.1024del) in the general population?

ERCC2 p.Trp342fs (c.1024del) is very rare (popmax 0.00273%, afr) (gnomAD).

ERCC2 p.Trp342fs

c.1024del · rs1040480735 · VCV2675052

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00273%, afr)

Conditions

cerebrooculofacioskeletal syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.7	GERP 1.8, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00273% African / African-American · 2/73,394 alleles

Filtering AF 0.000452% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000169%

Overall 0.000129% 2/1,547,152 alleles · very rare

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.Trp342fs
Coding: c.1024del
MANE Select: NM_000400
dbSNP: rs1040480735
Type: Deletion
Location: chr19:45363837 (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 342: an α-helix

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

Disease context

cerebrooculofacioskeletal syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERCC2 c.106-5_142del Likely pathogenic ★★ same condition
ERCC2 c.1347_1377+7del Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.2047-13_2048del Likely pathogenic ★★ same condition
ERCC2 c.2190+1del Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.594+2_594+5del Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Arg196_Tyr197insTer Pathogenic ★★ same condition
ERCC2 p.Arg669fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Gln662fs 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-trp342fs (accessed [today's date]).

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