Is ERCC6 p.Phe427= (c.1281C>T) pathogenic?

ERCC6 p.Phe427= (c.1281C>T) is classified Likely benign in ERCC6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-04-06). Very rare (popmax 0.0011%, sas); Associated with de Sanctis-Cacchione syndrome.

What condition is associated with ERCC6 p.Phe427= (c.1281C>T)?

ERCC6 p.Phe427= (c.1281C>T) is associated with de Sanctis-Cacchione syndrome, cerebrooculofacioskeletal syndrome 1, Cockayne syndrome type 2 (ClinVar).

How common is ERCC6 p.Phe427= (c.1281C>T) in the general population?

ERCC6 p.Phe427= (c.1281C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

ERCC6 p.Phe427=

c.1281C>T · rs267602508 · VCV77973

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

de Sanctis-Cacchione syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.063	GERP -2.6
Overall
CADD	2.598	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,066 alleles

Overall 6.2e-05% 1/1,613,890 alleles · very rare exomes 1/1,461,836 · genomes 0/152,054 · joint denominator

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.Phe427=
Coding: c.1281C>T
MANE Select: NM_000124
dbSNP: rs267602508
Type: single nucleotide variant
Location: chr10:49524149 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 427: the 'disordered' region; the 'n-terminal domain; essential for its chromatin remodeling activity' region

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

Disease context

de Sanctis-Cacchione syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebrooculofacioskeletal syndrome 1 Cockayne syndrome type 2

Similar variants

ERCC6 p.Phe427Ser Uncertain significance ★ ⚠ same residue
ERCC6 c.1397+1G>C Likely pathogenic ★★ same condition
ERCC6 c.1526+1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC6 c.2169+1G>A Likely pathogenic ★★ same condition
ERCC6 c.2170-1G>A Pathogenic/Likely pathogenic ★★ same condition
ERCC6 c.2286+1G>A Pathogenic/Likely pathogenic ★★ same condition
ERCC6 c.2287-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC6 c.2599-26A>G 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/ercc6-p-phe427 (accessed [today's date]).

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