Is ERCC2 p.Arg695Cys (c.2083C>T) pathogenic?

ERCC2 p.Arg695Cys (c.2083C>T) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-10-08). AlphaMissense: likely benign (0.2807); Ultra-rare (popmax 0.0217%, amr); Associated with Inborn genetic diseases.

What condition is associated with ERCC2 p.Arg695Cys (c.2083C>T)?

ERCC2 p.Arg695Cys (c.2083C>T) is associated with Inborn genetic diseases, xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 p.Arg695Cys (c.2083C>T) in the general population?

ERCC2 p.Arg695Cys (c.2083C>T) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about ERCC2 p.Arg695Cys (c.2083C>T)?

AlphaMissense predicts likely benign (score 0.2807) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg695Cys

c.2083C>T · rs201392911 · VCV134101

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2807 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2807	likely benign
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -11.62	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	34.0	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 0.0217% Admixed American · 13/60,018 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0162%

Overall 0.0173% 280/1,614,088 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,617
African / African-American	0.0213%	4,689
European (non-Finnish)	0.0192%	5,221
South Asian	0.0154%	6,506
Remaining individualsnot grpmax-eligible	0.0128%	7,813
East Asian	0.00446%	22,440
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Arg695Cys
Coding: c.2083C>T
MANE Select: NM_000400
dbSNP: rs201392911
Type: single nucleotide variant
Location: chr19:45352316 (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 695: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group D

Similar variants

ERCC2 p.Arg695His Uncertain significance ★★ ⚠ same residue
ERCC2 p.Arg695Leu Uncertain significance ★ ⚠ same residue
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1480-2A>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1666-2A>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1759-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.183+2T>A Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.361-1G>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-arg695cys (accessed [today's date]).

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