Is ERCC4 p.Arg589Trp (c.1765C>T) pathogenic?

ERCC4 p.Arg589Trp (c.1765C>T) is classified Pathogenic/Likely pathogenic in ERCC4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.9688); Ultra-rare (popmax 0.0167%, amr); Associated with ERCC4-related disorder.

What condition is associated with ERCC4 p.Arg589Trp (c.1765C>T)?

ERCC4 p.Arg589Trp (c.1765C>T) is associated with ERCC4-related disorder, xeroderma pigmentosum group F, XFE progeroid syndrome (ClinVar).

How common is ERCC4 p.Arg589Trp (c.1765C>T) in the general population?

ERCC4 p.Arg589Trp (c.1765C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about ERCC4 p.Arg589Trp (c.1765C>T)?

AlphaMissense predicts likely pathogenic (score 0.9688) — an in-silico prediction, not a clinical call.

ERCC4 p.Arg589Trp

c.1765C>T · rs147105770 · VCV55829

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9688 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ERCC4-related disorder

Computational evidence

Protein change
AlphaMissense	0.9688	likely pathogenic ✓ concordant with ClinVar · top 9% in ERCC4
REVEL	0.75	pathogenic-leaning
SaProt	LLR -14.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.20	donor loss · deltas
Constraint at this position
Conservation	phyloP 1.8	GERP 0.61, phastCons 0.93
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	25.8	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 0.0167% Admixed American · 10/59,982 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.0129% 209/1,613,958 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,998
European (non-Finnish)	0.0163%	6,146
Remaining individualsnot grpmax-eligible	0.0064%	15,621
African / African-American	0.00401%	24,965

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: ERCC4
Protein: p.Arg589Trp
Coding: c.1765C>T
MANE Select: NM_005236
dbSNP: rs147105770
Type: single nucleotide variant
Location: chr16:13935697 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.60 · 13 PDB
Residue 589: a UniProt-annotated variant site (in xpf/cs)

Full ERCC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ERCC4-related disorder

Also linked: xeroderma pigmentosum group F XFE progeroid syndrome Fanconi anemia complementation group Q autosomal recessive cerebellar ataxia Cockayne syndrome xeroderma pigmentosum xeroderma pigmentosum, type F/Cockayne syndrome

Similar variants

ERCC4 p.Arg589Gly Uncertain significance ★ ⚠ same residue
ERCC4 p.Arg589= Likely benign ★ same residue
ERCC4 c.1102+1G>T Likely pathogenic ★★ same condition
ERCC4 c.793-2A>G Pathogenic ★★ same condition
ERCC4 p.Arg20Ter Pathogenic ★★ same condition
ERCC4 p.Arg689Ser Likely pathogenic ★★ same condition
ERCC4 p.Arg772Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Cys236Arg 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/ercc4-p-arg589trp (accessed [today's date]).

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