Is ERCC3 p.Asp474fs (c.1421dup) pathogenic?

ERCC3 p.Asp474fs (c.1421dup) is classified Pathogenic/Likely pathogenic in ERCC3 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-12-30). Ultra-rare (popmax 0.0129%, nfe); Associated with Autosomal recessive ERCC3-related disorders.

What condition is associated with ERCC3 p.Asp474fs (c.1421dup)?

ERCC3 p.Asp474fs (c.1421dup) is associated with Autosomal recessive ERCC3-related disorders, xeroderma pigmentosum group B, trichothiodystrophy 2, photosensitive (ClinVar).

How common is ERCC3 p.Asp474fs (c.1421dup) in the general population?

ERCC3 p.Asp474fs (c.1421dup) is ultra-rare (popmax 0.0129%, nfe) (gnomAD).

ERCC3 p.Asp474fs

c.1421dup · rs587778281 · VCV134130

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0129%, nfe)

Conditions

Autosomal recessive ERCC3-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.88	GERP 1.1, phastCons 0.97
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0129% European (non-Finnish) · 152/1,180,036 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00985% 159/1,614,100 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0129%	7,763
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Admixed American	0.00333%	29,999
African / African-American	0.00133%	74,940

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.Asp474fs
Coding: c.1421dup
MANE Select: NM_000122
dbSNP: rs587778281
Type: Duplication
Location: chr2:127280552 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 474: the helicase atp-binding domain; a β-strand

Full ERCC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Autosomal recessive ERCC3-related disorders

Also linked: xeroderma pigmentosum group B trichothiodystrophy 2, photosensitive xeroderma pigmentosum

Similar variants

ERCC3 p.Trp374Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Asp81fs Likely pathogenic ★ same condition
ERCC3 p.Glu588fs Conflicting classifications of pathogenicity ★ same condition
ERCC3 c.1828-1G>C Likely pathogenic ★★ same condition
ERCC3 c.471+1G>A Pathogenic ★★ same condition
ERCC3 c.657+1G>A Likely pathogenic ★★ same condition
ERCC3 p.Arg109Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Arg195Ter 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/ercc3-p-asp474fs (accessed [today's date]).

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