Is ERCC2 p.Gln555Ter (c.1663C>T) pathogenic?

ERCC2 p.Gln555Ter (c.1663C>T) is classified Pathogenic/Likely pathogenic in ERCC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-12). Very rare (popmax 0.00133%, afr); Associated with xeroderma pigmentosum.

What condition is associated with ERCC2 p.Gln555Ter (c.1663C>T)?

ERCC2 p.Gln555Ter (c.1663C>T) is associated with xeroderma pigmentosum, cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Gln555Ter (c.1663C>T) in the general population?

ERCC2 p.Gln555Ter (c.1663C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Xeroderma pigmentosum inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ERCC2 p.Gln555Ter

c.1663C>T · rs753505084 · VCV2675042

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 17 of 23
Splicing
SpliceAI	Δ0.74	donor gain · deltas
Pangolin	Δ0.26	gain · loss 0.14 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.8	GERP 1.5, phastCons 1
Overall
CADD	61.0	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 0.00133% African / African-American · 1/75,030 alleles

Overall 0.000137% 2/1,461,594 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,030
European (non-Finnish)	8.48e-05%	1,179,908

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.Gln555Ter
Coding: c.1663C>T
MANE Select: NM_000400
dbSNP: rs753505084
Type: single nucleotide variant
Location: chr19:45354732 (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 555: the 'mediates interaction with mms19' region

Full ERCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

xeroderma pigmentosum — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebrooculofacioskeletal syndrome 2

For Xeroderma pigmentosum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

MAG p.Pro555= Likely benign ★ 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-gln555ter (accessed [today's date]).

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