Is ERCC2 p.Ter761Ser (c.2282G>C) pathogenic?

ERCC2 p.Ter761Ser (c.2282G>C) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-04). Ultra-rare (popmax 0.0111%, eas); Associated with xeroderma pigmentosum group D.

What condition is associated with ERCC2 p.Ter761Ser (c.2282G>C)?

ERCC2 p.Ter761Ser (c.2282G>C) is associated with xeroderma pigmentosum group D, trichothiodystrophy 1, photosensitive, cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Ter761Ser (c.2282G>C) in the general population?

ERCC2 p.Ter761Ser (c.2282G>C) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

ERCC2 p.Ter761Ser

Q: How is Xeroderma pigmentosum-Cockayne syndrome complex inherited?

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

c.2282G>C · rs966558219 · VCV1493811

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

stop-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

xeroderma pigmentosum group D

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	stop-loss	predicted loss-of-function
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -0.12
Overall
CADD	10.65	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 0.0111% East Asian · 5/44,882 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000547% 8/1,461,640 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,976
Remaining individualsnot grpmax-eligible	0.0016%	62,506
South Asian	0.0011%	91,084
European (non-Finnish)	8.47e-05%	1,179,956

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.Ter761Ser
Coding: c.2282G>C
MANE Select: NM_000400
dbSNP: rs966558219
Type: single nucleotide variant
Location: chr19:45351630 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB

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

Disease context

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

Also linked: trichothiodystrophy 1, photosensitive cerebrooculofacioskeletal syndrome 2

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

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
ERCC2 c.1666-1G>A 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-ter761ser (accessed [today's date]).

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