Is ERCC2 p.Ser578fs (c.1732_1741del) pathogenic?

ERCC2 p.Ser578fs (c.17321741del) is classified Pathogenic/Likely pathogenic in ERCC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-31). Very rare (popmax 8.48e-05%, nfe); Associated with cerebrooculofacioskeletal syndrome 2.

What condition is associated with ERCC2 p.Ser578fs (c.1732_1741del)?

ERCC2 p.Ser578fs (c.1732_1741del) is associated with cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Ser578fs (c.1732_1741del) in the general population?

ERCC2 p.Ser578fs (c.1732_1741del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

ERCC2 p.Ser578fs

c.1732_1741del · rs1971888879 · VCV2675038

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 8.48e-05%, nfe)

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 18 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 0.65, 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 8.48e-05% European (non-Finnish) · 1/1,179,818 alleles

Overall 0.000124% 2/1,613,496 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)grpmax	8.48e-05%	1,179,818

Remaining individuals 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.Ser578fs
Coding: c.1732_1741del
MANE Select: NM_000400
dbSNP: rs1971888879
Type: Deletion
Location: chr19:45353259 (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 578: an α-helix; the 'mediates interaction with mms19' region

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-ser578fs (accessed [today's date]).

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