Is ERCC3 p.Gln586fs (c.1757del) pathogenic?

ERCC3 p.Gln586fs (c.1757del) is classified Pathogenic/Likely pathogenic in ERCC3 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-03). Ultra-rare (popmax 0.0215%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ERCC3 p.Gln586fs (c.1757del)?

ERCC3 p.Gln586fs (c.1757del) is associated with Inborn genetic diseases, xeroderma pigmentosum group B, trichothiodystrophy 2, photosensitive (ClinVar).

How common is ERCC3 p.Gln586fs (c.1757del) in the general population?

ERCC3 p.Gln586fs (c.1757del) is ultra-rare (popmax 0.0215%, nfe) (gnomAD).

ERCC3 p.Gln586fs

c.1757del · rs753182861 · VCV1070632

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0215%, nfe)

Conditions

Inborn genetic diseases

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 11 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.26	GERP -4.3, phastCons 0.24
Overall
CADD	35.0	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 0.0215% European (non-Finnish) · 253/1,178,784 alleles

Filtering AF 0.0193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.0175% 283/1,612,746 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0336%	2,974
European (non-Finnish)grpmax	0.0215%	4,659
African / African-American	0.00533%	18,756
Finnishnot grpmax-eligible	0.00312%	32,016
South Asian	0.0022%	45,516
Admixed American	0.00167%	60,008

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gln586fs
Coding: c.1757del
MANE Select: NM_000122
dbSNP: rs753182861
Type: Deletion
Location: chr2:127272935 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 586: the helicase c-terminal domain; 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

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

Similar variants

ERCC3 p.Asp237fs Likely pathogenic ★ same condition
ERCC3 p.Glu372fs Likely pathogenic ★ same condition
ERCC3 p.Gly611fs Likely pathogenic ★ same condition
ERCC3 p.Ser269_Phe270insTer Pathogenic ★ same condition
ERCC3 p.Met759_Tyr761del Uncertain significance ★ 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

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-gln586fs (accessed [today's date]).

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