Is ERCC6 p.Asp128= (c.384C>T) pathogenic?

ERCC6 p.Asp128= (c.384C>T) is classified Conflicting classifications of pathogenicity in ERCC6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-08). Ultra-rare (popmax 0.0908%, afr); Associated with age related macular degeneration 5.

What condition is associated with ERCC6 p.Asp128= (c.384C>T)?

ERCC6 p.Asp128= (c.384C>T) is associated with age related macular degeneration 5, cerebrooculofacioskeletal syndrome 1, Cockayne syndrome type 2 (ClinVar).

How common is ERCC6 p.Asp128= (c.384C>T) in the general population?

ERCC6 p.Asp128= (c.384C>T) is ultra-rare (popmax 0.0908%, afr) (gnomAD).

ERCC6 p.Asp128=

c.384C>T · rs146165518 · VCV300094

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0908%, afr)

Conditions

age related macular degeneration 5

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 -4.8	GERP -3.6
Overall
CADD	0.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0908% African / African-American · 68/74,928 alleles

Filtering AF 0.0734% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0671%

Overall 0.00558% 90/1,614,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0908%	1,102
Remaining individualsnot grpmax-eligible	0.0112%	8,927
Admixed American	0.00667%	15,002
East Asian	0.00223%	44,896
European (non-Finnish)	0.000847%	118,005

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.Asp128=
Coding: c.384C>T
MANE Select: NM_000124
dbSNP: rs146165518
Type: single nucleotide variant
Location: chr10:49532581 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 128: the 'n-terminal domain; essential for its chromatin remodeling activity' region; an α-helix

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

Disease context

Also linked: cerebrooculofacioskeletal syndrome 1 Cockayne syndrome type 2

Similar variants

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
ERCC6 c.2830-2A>G 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-asp128 (accessed [today's date]).

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