Is ERCC2 p.Val623fs (c.1867dup) pathogenic?

ERCC2 p.Val623fs (c.1867dup) is classified Pathogenic/Likely pathogenic in ERCC2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-06-29). Very rare (popmax 0.00971%, nfe); Associated with ERCC2-related disorder.

What condition is associated with ERCC2 p.Val623fs (c.1867dup)?

ERCC2 p.Val623fs (c.1867dup) is associated with ERCC2-related disorder, xeroderma pigmentosum group D, trichothiodystrophy 1, photosensitive (ClinVar).

How common is ERCC2 p.Val623fs (c.1867dup) in the general population?

ERCC2 p.Val623fs (c.1867dup) is very rare (popmax 0.00971%, nfe) (gnomAD).

ERCC2 p.Val623fs

c.1867dup · rs756630156 · VCV1363277

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00971%, nfe)

Conditions

ERCC2-related disorder

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 20 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Overall
CADD	34.0	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 0.00971% European (non-Finnish) · 114/1,174,264 alleles

Filtering AF 0.00822% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00764%

Overall 0.0075% 120/1,600,704 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00971%	10,301
Remaining individualsnot grpmax-eligible	0.00643%	15,555
Admixed American	0.0017%	58,946
African / African-American	0.0014%	71,232

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.Val623fs
Coding: c.1867dup
MANE Select: NM_000400
dbSNP: rs756630156
Type: Duplication
Location: chr19:45352780 (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 623: the 'mediates interaction with mms19' region

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

Disease context

Also linked: xeroderma pigmentosum group D trichothiodystrophy 1, photosensitive cerebrooculofacioskeletal syndrome 2 trichothiodystrophy

Similar variants

ERCC2 p.Val623Ile Uncertain significance ★★ ⚠ same residue
ERCC2 c.1377+1dup Likely pathogenic ★★ same condition
ERCC2 c.1479+2dup Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Ala600fs Likely pathogenic ★★ same condition
ERCC2 p.His729fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Ile432fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Leu337fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Lys692fs 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-val623fs (accessed [today's date]).

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