Is ERCC2 p.Phe568fs (c.1703_1704del) pathogenic?

ERCC2 p.Phe568fs (c.17031704del) is classified Pathogenic/Likely pathogenic in ERCC2 (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-02-02). Ultra-rare (popmax 0.0105%, nfe); Associated with ERCC2-related disorder.

What condition is associated with ERCC2 p.Phe568fs (c.1703_1704del)?

ERCC2 p.Phe568fs (c.1703_1704del) is associated with ERCC2-related disorder, xeroderma pigmentosum group D, trichothiodystrophy 1, photosensitive (ClinVar).

How common is ERCC2 p.Phe568fs (c.1703_1704del) in the general population?

ERCC2 p.Phe568fs (c.1703_1704del) is ultra-rare (popmax 0.0105%, nfe) (gnomAD).

ERCC2 p.Phe568fs

c.1703_1704del · rs587778271 · VCV134095

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0105%, 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 18 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 0.73, phastCons 1
Overall
CADD	35.0	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 0.0105% European (non-Finnish) · 124/1,179,968 alleles

Filtering AF 0.00901% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00842%

Overall 0.00886% 143/1,613,976 alleles · ultra-rare exomes 114/1,461,844 · genomes 29/152,132 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0141%	7,114
European (non-Finnish)grpmax	0.0105%	9,516
Remaining individualsnot grpmax-eligible	0.008%	12,501
Admixed American	0.00667%	14,999
African / African-American	0.00133%	74,974

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe568fs
Coding: c.1703_1704del
MANE Select: NM_000400
dbSNP: rs587778271
Type: Deletion
Location: chr19:45353296 (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 568: a β-strand; 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 leukodystrophy xeroderma pigmentosum

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-phe568fs (accessed [today's date]).

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