Is ERCC2 p.Val714fs (c.2141_2148del) pathogenic?

ERCC2 p.Val714fs (c.21412148del) is classified Pathogenic/Likely pathogenic in ERCC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-06). Very rare (popmax 0.000508%, nfe); Associated with xeroderma pigmentosum.

What condition is associated with ERCC2 p.Val714fs (c.2141_2148del)?

ERCC2 p.Val714fs (c.2141_2148del) is associated with xeroderma pigmentosum, xeroderma pigmentosum group D, trichothiodystrophy 1, photosensitive (ClinVar).

How common is ERCC2 p.Val714fs (c.2141_2148del) in the general population?

ERCC2 p.Val714fs (c.2141_2148del) is very rare (popmax 0.000508%, nfe) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

ERCC2 p.Val714fs

c.2141_2148del · rs1172840777 · VCV1705082

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (22 of 23, 42 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,180,008 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,786 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.Val714fs
Coding: c.2141_2148del
MANE Select: NM_000400
dbSNP: rs1172840777
Type: Deletion
Location: chr19:45352251 (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 714: 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 trichothiodystrophy 1, photosensitive cerebrooculofacioskeletal syndrome 2

For Xeroderma pigmentosum (Orphanet):

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

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-val714fs (accessed [today's date]).

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