Is ERCC2 p.Phe720fs (c.2156_2159dup) pathogenic?

ERCC2 p.Phe720fs (c.21562159dup) is classified Pathogenic/Likely pathogenic in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-06). Absent from gnomAD; Associated with cerebrooculofacioskeletal syndrome 2.

What condition is associated with ERCC2 p.Phe720fs (c.2156_2159dup)?

ERCC2 p.Phe720fs (c.2156_2159dup) is associated with cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Phe720fs (c.2156_2159dup) in the general population?

ERCC2 p.Phe720fs (c.2156_2159dup) is absent from gnomAD (gnomAD).

ERCC2 p.Phe720fs

c.2156_2159dup · rs2513997582 · VCV2765458

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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	escapes	premature termination codon within the last 50 nt of the penultimate exon (22 of 23, 30 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 7.5	GERP 0.47, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ERCC2
Protein: p.Phe720fs
Coding: c.2156_2159dup
MANE Select: NM_000400
dbSNP: rs2513997582
Type: Duplication
Location: chr19:45352239 (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 720: an α-helix; a UniProt-annotated variant site (in xp-d and ttd1; no longer interacts with gtf2h2/p44; has 5'-3' helicase activity)

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.1377+1dup Likely pathogenic ★★ same condition
ERCC2 c.1479+2dup Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Ala600fs 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
ERCC2 p.Tyr625fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Val623fs 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-phe720fs (accessed [today's date]).

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