Is ERCC2 p.Ala667fs (c.1999_2000delinsA) pathogenic?

ERCC2 p.Ala667fs (c.19992000delinsA) is classified Likely pathogenic in ERCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-25). No gnomAD frequency available for this variant; Associated with cerebrooculofacioskeletal syndrome 2.

What condition is associated with ERCC2 p.Ala667fs (c.1999_2000delinsA)?

ERCC2 p.Ala667fs (c.1999_2000delinsA) is associated with cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Ala667fs (c.1999_2000delinsA) in the general population?

ERCC2 p.Ala667fs (c.1999_2000delinsA) is no gnomAD frequency available for this variant (gnomAD).

ERCC2 p.Ala667fs

c.1999_2000delinsA · rs2513999250 · VCV3241394

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

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	predicted	premature termination codon in exon 21 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 1.2, 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.Ala667fs
Coding: c.1999_2000delinsA
MANE Select: NM_000400
dbSNP: rs2513999250
Type: Indel
Location: chr19:45352552 (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 667: an α-helix

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.948_949+2delinsCCC Likely pathogenic ★★ same condition
ERCC2 p.Glu66Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Ala667= Likely benign ★★ same residue
ERCC2 p.Ala667Thr Uncertain significance ★ same residue
ERCC2 p.Ala667Val Uncertain significance ★ ⚠ same residue
ERCC2 c.106-5_142del Likely pathogenic ★★ same condition
ERCC2 c.1238-1G>C Likely pathogenic ★★ same condition
ERCC2 c.1308-2A>G 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-ala667fs (accessed [today's date]).

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