Is ERCC2 p.Arg730Leu (c.2189G>T) pathogenic?

ERCC2 p.Arg730Leu (c.2189G>T) is classified Uncertain significance in ERCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-12). AlphaMissense: likely benign (0.2643); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with ERCC2 p.Arg730Leu (c.2189G>T)?

ERCC2 p.Arg730Leu (c.2189G>T) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC2 p.Arg730Leu (c.2189G>T) in the general population?

ERCC2 p.Arg730Leu (c.2189G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ERCC2 p.Arg730Leu (c.2189G>T)?

AlphaMissense predicts likely benign (score 0.2643) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg730Leu

c.2189G>T · rs759412116 · VCV2479673

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2643	likely benign
REVEL	0.539	indeterminate
SaProt	LLR -6.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
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	24.1	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 0.00133% African / African-American · 1/75,040 alleles

Overall 6.84e-05% 1/1,461,344 alleles · very rare

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.Arg730Leu
Coding: c.2189G>T
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

Similar variants

ERCC2 p.Arg730Gln 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 p.Ala725Pro Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Arg616Pro Pathogenic ★★ same condition
ERCC2 p.Ala108Thr Uncertain significance ★★ ⚠ same condition
ERCC2 p.Ala144Val Uncertain significance ★★ ⚠ 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-arg730leu (accessed [today's date]).

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