Is ERCC6 p.Lys1198= (c.3594A>G) pathogenic?

ERCC6 p.Lys1198= (c.3594A>G) is classified Conflicting classifications of pathogenicity in ERCC6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-18). Very rare (popmax 0.00167%, amr); Associated with age related macular degeneration 5.

What condition is associated with ERCC6 p.Lys1198= (c.3594A>G)?

ERCC6 p.Lys1198= (c.3594A>G) is associated with age related macular degeneration 5, cerebrooculofacioskeletal syndrome 1, Cockayne syndrome type 2 (ClinVar).

How common is ERCC6 p.Lys1198= (c.3594A>G) in the general population?

ERCC6 p.Lys1198= (c.3594A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

ERCC6 p.Lys1198=

c.3594A>G · rs374791168 · VCV300045

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 -0.68	GERP -4
Overall
CADD	0.354	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,006 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000867% 14/1,614,104 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,006
European (non-Finnish)	0.0011%	90,770

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.Lys1198=
Coding: c.3594A>G
MANE Select: NM_000124
dbSNP: rs374791168
Type: single nucleotide variant
Location: chr10:49470366 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 1198: the 'disordered' region

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 p.Lys1198fs 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-lys1198 (accessed [today's date]).

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