Is ERCC3 p.Arg283His (c.848G>A) pathogenic?

ERCC3 p.Arg283His (c.848G>A) is classified Uncertain significance in ERCC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-18). AlphaMissense: likely benign (0.2106); Ultra-rare (popmax 0.0168%, mid); Associated with Inborn genetic diseases.

What condition is associated with ERCC3 p.Arg283His (c.848G>A)?

ERCC3 p.Arg283His (c.848G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC3 p.Arg283His (c.848G>A) in the general population?

ERCC3 p.Arg283His (c.848G>A) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about ERCC3 p.Arg283His (c.848G>A)?

AlphaMissense predicts likely benign (score 0.2106) — an in-silico prediction, not a clinical call.

ERCC3 p.Arg283His

c.848G>A · rs749390618 · VCV1937211

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2106 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2106	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -11.20	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	26.6	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 0.0168% Middle Eastern · 1/5,970 alleles

Overall 0.000205% 3/1,461,440 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,970
Admixed American	0.00167%	60,012
European (non-Finnish)	8.48e-05%	1,179,715

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: ERCC3
Protein: p.Arg283His
Coding: c.848G>A
MANE Select: NM_000122
dbSNP: rs749390618
Type: single nucleotide variant
Location: chr2:127288839 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 283: an α-helix

Full ERCC3 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

ERCC3 p.Arg283Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ERCC3 p.Gln711Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Ala120Val Uncertain significance ★★ ⚠ same condition
ERCC3 p.Arg109Gln Uncertain significance ★★ ⚠ same condition
ERCC3 p.Arg334His Uncertain significance ★★ ⚠ same condition
ERCC3 p.Arg453Lys Uncertain significance ★★ ⚠ same condition
ERCC3 p.Arg634Cys Uncertain significance ★★ ⚠ same condition
ERCC3 p.Arg743Cys 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/ercc3-p-arg283his (accessed [today's date]).

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