Is ERCC2 p.Val340fs (c.1017_1018insTC) pathogenic?

ERCC2 p.Val340fs (c.10171018insTC) is classified Pathogenic in ERCC2 (ClinVar, Single submitter, 1 submitter). Associated with xeroderma pigmentosum group D.

What condition is associated with ERCC2 p.Val340fs (c.1017_1018insTC)?

ERCC2 p.Val340fs (c.1017_1018insTC) is associated with xeroderma pigmentosum group D, trichothiodystrophy 1, photosensitive, cerebrooculofacioskeletal syndrome 2 (ClinVar).

ERCC2 p.Val340fs

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

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

c.1017_1018insTC · VCV3382695

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

xeroderma pigmentosum group D

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 2.6	GERP 1.8, phastCons 0.99

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

Variant & gene context

Gene: ERCC2
Protein: p.Val340fs
Coding: c.1017_1018insTC
MANE Select: NM_000400
Type: Insertion
Location: chr19:45363843 (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 340: an α-helix

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

Also linked: trichothiodystrophy 1, photosensitive cerebrooculofacioskeletal syndrome 2

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ERCC2 p.Val340Leu Uncertain significance ★★ ⚠ same residue
ERCC2 p.Asp131Ter Likely pathogenic ★ same condition
ERCC2 p.Thr460fs Likely pathogenic ★ same condition
ERCC2 p.Lys671fs Conflicting classifications of pathogenicity ★ same condition
ERCC2 p.Val340Met Uncertain significance ★ ⚠ same residue
ERCC2 p.Val476fs Uncertain significance ★ same condition
ERCC2 p.Val340= Likely benign ★ same residue
ERCC2 c.106-5_142del 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-val340fs (accessed [today's date]).

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