Is ERCC6 p.Pro70fs (c.207dup) pathogenic?

ERCC6 p.Pro70fs (c.207dup) is classified Pathogenic/Likely pathogenic in ERCC6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-03-06). Very rare (popmax 0.000169%, nfe); Associated with cerebrooculofacioskeletal syndrome 1.

What condition is associated with ERCC6 p.Pro70fs (c.207dup)?

ERCC6 p.Pro70fs (c.207dup) is associated with cerebrooculofacioskeletal syndrome 1, lung cancer, de Sanctis-Cacchione syndrome (ClinVar).

How common is ERCC6 p.Pro70fs (c.207dup) in the general population?

ERCC6 p.Pro70fs (c.207dup) is very rare (popmax 0.000169%, nfe) (gnomAD).

ERCC6 p.Pro70fs

c.207dup · rs1554794641 · VCV556870

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

cerebrooculofacioskeletal syndrome 1

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 2 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.1	GERP 0.18, phastCons 0.21

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,038 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,890 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: ERCC6
Protein: p.Pro70fs
Coding: c.207dup
MANE Select: NM_000124
dbSNP: rs1554794641
Type: Duplication
Location: chr10:49532757 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 70: the 'n-terminal domain; essential for its chromatin remodeling activity' region

Full ERCC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebrooculofacioskeletal syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lung cancer de Sanctis-Cacchione syndrome UV-sensitive syndrome 1 age related macular degeneration 5 premature ovarian failure 11 Cockayne syndrome type 2

Similar variants

ERCC6 p.Leu147fs Pathogenic ★★ same condition
ERCC6 p.Leu700fs Pathogenic/Likely pathogenic ★★ same condition
ERCC6 p.Ser429fs Pathogenic ★★ same condition
ERCC6 p.Thr1138fs Pathogenic ★★ same condition
ERCC6 p.Thr659fs Pathogenic ★★ same condition
ERCC6 p.Thr699fs Pathogenic ★★ same condition
ERCC6 p.Arg261fs Pathogenic ★ same condition
ERCC6 p.Cys617fs 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/ercc6-p-pro70fs (accessed [today's date]).

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