Is ERCC2 p.Trp696Ter (c.2087G>A) pathogenic?

ERCC2 p.Trp696Ter (c.2087G>A) is classified Likely pathogenic in ERCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-01). Very rare (popmax 0.000508%, nfe); Associated with cerebrooculofacioskeletal syndrome 2.

What condition is associated with ERCC2 p.Trp696Ter (c.2087G>A)?

ERCC2 p.Trp696Ter (c.2087G>A) is associated with cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Trp696Ter (c.2087G>A) in the general population?

ERCC2 p.Trp696Ter (c.2087G>A) is very rare (popmax 0.000508%, nfe) (gnomAD).

ERCC2 p.Trp696Ter

c.2087G>A · rs775446858 · VCV2675067

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Conditions

cerebrooculofacioskeletal syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 22 of 23
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Overall
CADD	51.0	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 0.000508% European (non-Finnish) · 6/1,180,026 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,806 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: ERCC2
Protein: p.Trp696Ter
Coding: c.2087G>A
MANE Select: NM_000400
dbSNP: rs775446858
Type: single nucleotide variant
Location: chr19:45352312 (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 696: 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 p.Trp696Arg Uncertain significance ★ ⚠ same residue
ERCC2 c.1238-1G>C Likely pathogenic ★★ same condition
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1378-1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1479+2T>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1480-1G>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1480-2A>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1544-1G>T 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-trp696ter (accessed [today's date]).

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