Is ERCC6 p.Ser1329fs (c.3983dup) pathogenic?

ERCC6 p.Ser1329fs (c.3983dup) is classified Pathogenic in ERCC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-21). Very rare (popmax 0.00288%, nfe).

How common is ERCC6 p.Ser1329fs (c.3983dup) in the general population?

ERCC6 p.Ser1329fs (c.3983dup) is very rare (popmax 0.00288%, nfe) (gnomAD).

ERCC6 p.Ser1329fs

c.3983dup · rs760027420 · VCV836041

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Overall
CADD	39.0	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 0.00288% European (non-Finnish) · 34/1,179,952 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00217% 35/1,612,686 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,705
Remaining individualsnot grpmax-eligible	0.0016%	62,360

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: ERCC6
Protein: p.Ser1329fs
Coding: c.3983dup
MANE Select: NM_000124
dbSNP: rs760027420
Type: Duplication
Location: chr10:49461351 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 1329: the 'disordered' region

Full ERCC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERCC6 p.Ser1329Ile Uncertain significance ★★ ⚠ same residue
ERCC6 p.Leu147fs Pathogenic ★★ same type
ERCC6 p.Leu700fs Pathogenic/Likely pathogenic ★★ same type
ERCC6 p.Pro70fs Pathogenic/Likely pathogenic ★★ same type
ERCC6 p.Ser429fs Pathogenic ★★ same type
ERCC6 p.Thr1138fs Pathogenic ★★ same type
ERCC6 p.Thr659fs Pathogenic ★★ same type
ERCC6 p.Thr699fs Pathogenic ★★ same type

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/ercc6-p-ser1329fs (accessed [today's date]).

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