Is ERCC5 p.Ser489fs (c.1463dup) pathogenic?

ERCC5 p.Ser489fs (c.1463dup) is classified Likely pathogenic in ERCC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-05). Very rare (popmax 0.000593%, nfe); Associated with cerebrooculofacioskeletal syndrome 3.

What condition is associated with ERCC5 p.Ser489fs (c.1463dup)?

ERCC5 p.Ser489fs (c.1463dup) is associated with cerebrooculofacioskeletal syndrome 3, xeroderma pigmentosum group G (ClinVar).

How common is ERCC5 p.Ser489fs (c.1463dup) in the general population?

ERCC5 p.Ser489fs (c.1463dup) is very rare (popmax 0.000593%, nfe) (gnomAD).

ERCC5 p.Ser489fs

c.1463dup · VCV3575653

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

cerebrooculofacioskeletal syndrome 3

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 looked up on this page · why
Constraint at this position
Conservation	phyloP 0.28	GERP -3.8
Overall
CADD	17.06	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 0.000593% European (non-Finnish) · 7/1,180,036 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,614,010 alleles · very rare

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: ERCC5
Protein: p.Ser489fs
Coding: c.1463dup
Type: Duplication
Location: chr13:102862611 (GRCh38)

Full ERCC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebrooculofacioskeletal syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group G

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/ercc5-p-ser489fs (accessed [today's date]).

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