Is ERCC2 p.Arg601Trp (c.1801C>T) pathogenic?

ERCC2 p.Arg601Trp (c.1801C>T) is classified Conflicting classifications of pathogenicity in ERCC2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2024-10-25). AlphaMissense: likely pathogenic (0.9961); Ultra-rare (popmax 0.0169%, mid); Associated with xeroderma pigmentosum group D.

What condition is associated with ERCC2 p.Arg601Trp (c.1801C>T)?

ERCC2 p.Arg601Trp (c.1801C>T) is associated with xeroderma pigmentosum group D, trichothiodystrophy 1, photosensitive, cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Arg601Trp (c.1801C>T) in the general population?

ERCC2 p.Arg601Trp (c.1801C>T) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

What do computational predictors say about ERCC2 p.Arg601Trp (c.1801C>T)?

AlphaMissense predicts likely pathogenic (score 0.9961) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg601Trp

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

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

c.1801C>T · rs753641926 · VCV893463

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9961 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum group D

Computational evidence

Protein change
AlphaMissense	0.9961	likely pathogenic · top 9% in ERCC2
REVEL	0.746	pathogenic-leaning
SaProt	LLR -17.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% Middle Eastern · 1/5,930 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00539% 87/1,613,314 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,930
South Asian	0.0154%	6,505
Remaining individualsnot grpmax-eligible	0.0112%	8,919
African / African-American	0.00535%	18,708
European (non-Finnish)	0.00475%	21,069
East Asian	0.00446%	22,437
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
Admixed American	0.00333%	29,998

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.Arg601Trp
Coding: c.1801C>T
MANE Select: NM_000400
dbSNP: rs753641926
Type: single nucleotide variant
Location: chr19:45353113 (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 601: the 'mediates interaction with mms19' region; a UniProt-annotated variant site (in xp-d)

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 p.Arg601Leu Pathogenic/Likely pathogenic ★★ same residue
ERCC2 p.Arg601Gln Uncertain significance ★★ ⚠ same residue
ERCC2 p.Arg601= 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

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-arg601trp (accessed [today's date]).

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