Is ERCC6 p.Lys1258= (c.3774A>G) pathogenic?

ERCC6 p.Lys1258= (c.3774A>G) is classified Benign/Likely benign in ERCC6 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Low-frequency (popmax 2.9%, afr); Associated with cerebrooculofacioskeletal syndrome 1.

What condition is associated with ERCC6 p.Lys1258= (c.3774A>G)?

ERCC6 p.Lys1258= (c.3774A>G) is associated with cerebrooculofacioskeletal syndrome 1, age related macular degeneration 5, Cockayne syndrome type 2 (ClinVar).

How common is ERCC6 p.Lys1258= (c.3774A>G) in the general population?

ERCC6 p.Lys1258= (c.3774A>G) is low-frequency (popmax 2.9%, afr) (gnomAD).

ERCC6 p.Lys1258=

c.3774A>G · rs35756610 · VCV300043

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.9%, afr)

Conditions

cerebrooculofacioskeletal syndrome 1

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 0.042	GERP -3.8, phastCons 0.96
Overall
CADD	8.112	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.9% African / African-American · 2,173/75,060 alleles

Filtering AF 2.79% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.75%

Overall 0.154% 2,485/1,614,072 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.9%	35
Admixed American	0.227%	441
Remaining individualsnot grpmax-eligible	0.184%	543
Middle Eastern	0.0495%	2,020
European (non-Finnish)	0.00458%	21,850
South Asian	0.00329%	30,357
East Asian	0.00223%	44,888

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.Lys1258=
Coding: c.3774A>G
MANE Select: NM_000124
dbSNP: rs35756610
Type: single nucleotide variant
Location: chr10:49470186 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB

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

Disease context

cerebrooculofacioskeletal syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 5 Cockayne syndrome type 2

Similar variants

ERCC6 p.Lys1258fs Likely pathogenic ★ 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-lys1258 (accessed [today's date]).

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