Is ERCC6 p.Phe427Ser (c.1280T>C) pathogenic?

ERCC6 p.Phe427Ser (c.1280T>C) is classified Uncertain significance in ERCC6 (ClinVar, Single submitter, 2 submitters; last evaluated 2018-01-13). AlphaMissense: likely benign (0.0873); Very rare (popmax 0.00223%, eas); Associated with age related macular degeneration 5.

What condition is associated with ERCC6 p.Phe427Ser (c.1280T>C)?

ERCC6 p.Phe427Ser (c.1280T>C) is associated with age related macular degeneration 5, cerebrooculofacioskeletal syndrome 1, de Sanctis-Cacchione syndrome (ClinVar).

How common is ERCC6 p.Phe427Ser (c.1280T>C) in the general population?

ERCC6 p.Phe427Ser (c.1280T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ERCC6 p.Phe427Ser (c.1280T>C)?

AlphaMissense predicts likely benign (score 0.0873) — an in-silico prediction, not a clinical call.

ERCC6 p.Phe427Ser

c.1280T>C · rs886047038 · VCV300082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0873 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

age related macular degeneration 5

Computational evidence

Protein change
AlphaMissense	0.0873	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -5.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -1.6
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	12.69	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,884 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,614,014 alleles · very rare exomes 5/1,461,786 · genomes 0/152,228 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000254%	393,337

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.Phe427Ser
Coding: c.1280T>C
MANE Select: NM_000124
dbSNP: rs886047038
Type: single nucleotide variant
Location: chr10:49524150 (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

Also linked: cerebrooculofacioskeletal syndrome 1 de Sanctis-Cacchione syndrome Cockayne syndrome type 2

Similar variants

ERCC6 p.Phe427= Likely benign 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-phe427ser (accessed [today's date]).

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