Is ERCC2 p.Arg730Gln (c.2189G>A) pathogenic?

ERCC2 p.Arg730Gln (c.2189G>A) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-04-18). AlphaMissense: likely benign (0.0888); Ultra-rare (popmax 0.0183%, amr); Associated with Inborn genetic diseases.

What condition is associated with ERCC2 p.Arg730Gln (c.2189G>A)?

ERCC2 p.Arg730Gln (c.2189G>A) is associated with Inborn genetic diseases, xeroderma pigmentosum (ClinVar).

How common is ERCC2 p.Arg730Gln (c.2189G>A) in the general population?

ERCC2 p.Arg730Gln (c.2189G>A) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about ERCC2 p.Arg730Gln (c.2189G>A)?

AlphaMissense predicts likely benign (score 0.0888) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg730Gln

c.2189G>A · rs759412116 · VCV1206329

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0888 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0888	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/59,998 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00366% 59/1,613,628 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,454
South Asian	0.011%	9,104
Remaining individualsnot grpmax-eligible	0.0064%	15,614
European (non-Finnish)	0.0028%	35,755
Finnishnot grpmax-eligible	0.00157%	63,886

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.Arg730Gln
Coding: c.2189G>A
MANE Select: NM_000400
dbSNP: rs759412116
Type: single nucleotide variant
Location: chr19:45352210 (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 730: a UniProt-annotated variant site (in xp-d and ttd1; no longer interacts with gtf2h2/p44; has 5'-3' helicase activity)

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

Similar variants

ERCC2 p.Arg730Leu Uncertain significance ★ ⚠ same residue
ERCC2 p.Arg730Pro Uncertain significance ★ ⚠ same residue
ERCC2 p.Arg730Trp Uncertain significance ★ ⚠ same residue
ERCC2 p.Arg730= Likely benign ★ same residue
ERCC2 c.816-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Ala717Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
ERCC2 p.Ala725Pro Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Arg511Gln 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-arg730gln (accessed [today's date]).

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