Is ERCC4 p.Arg153Pro (c.458G>C) pathogenic?

ERCC4 p.Arg153Pro (c.458G>C) is classified Pathogenic in ERCC4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2006-12-21). AlphaMissense: likely pathogenic (0.9982); Very rare (popmax 0.00223%, eas); Associated with XFE progeroid syndrome.

What condition is associated with ERCC4 p.Arg153Pro (c.458G>C)?

ERCC4 p.Arg153Pro (c.458G>C) is associated with XFE progeroid syndrome (ClinVar).

How common is ERCC4 p.Arg153Pro (c.458G>C) in the general population?

ERCC4 p.Arg153Pro (c.458G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ERCC4 p.Arg153Pro (c.458G>C)?

AlphaMissense predicts likely pathogenic (score 0.9982) — an in-silico prediction, not a clinical call.

ERCC4 p.Arg153Pro

c.458G>C · rs121913050 · VCV16581

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

XFE progeroid syndrome

Computational evidence

Protein change
AlphaMissense	0.9982	likely pathogenic ✓ concordant with ClinVar · top 1% in ERCC4
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -17.91	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	33.0	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 0.00223% East Asian · 1/44,878 alleles

Overall 0.000124% 2/1,613,896 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,878
Admixed American	0.00167%	59,998

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.Arg153Pro
Coding: c.458G>C
MANE Select: NM_005236
dbSNP: rs121913050
Type: single nucleotide variant
Location: chr16:13926630 (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 153: the 'helicase-like' region; a UniProt-annotated variant site (in xfeps)

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

Disease context

XFE progeroid syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERCC4 p.Arg153Cys Uncertain significance ★ ⚠ same residue
ERCC4 p.Arg153His Uncertain significance ★ ⚠ same residue
ERCC4 p.Arg589Trp Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Arg689Ser Likely pathogenic ★★ same condition
ERCC4 p.Arg772Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Cys723Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Ser459Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Trp450Ter 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-arg153pro (accessed [today's date]).

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