Is ERCC6 p.Lys607Arg (c.1820A>G) pathogenic?

ERCC6 p.Lys607Arg (c.1820A>G) is classified Uncertain significance in ERCC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.1128); Very rare (popmax 0.0011%, nfe); Associated with Cockayne syndrome type 2.

What condition is associated with ERCC6 p.Lys607Arg (c.1820A>G)?

ERCC6 p.Lys607Arg (c.1820A>G) is associated with Cockayne syndrome type 2, cerebrooculofacioskeletal syndrome 1, age related macular degeneration 5 (ClinVar).

How common is ERCC6 p.Lys607Arg (c.1820A>G) in the general population?

ERCC6 p.Lys607Arg (c.1820A>G) is very rare (popmax 0.0011%, nfe) (gnomAD).

How is Cockayne syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ERCC6 p.Lys607Arg (c.1820A>G)?

AlphaMissense predicts likely benign (score 0.1128) — an in-silico prediction, not a clinical call.

ERCC6 p.Lys607Arg

c.1820A>G · rs200832611 · VCV452965

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1128 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cockayne syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.1128	likely benign
REVEL	0.671	pathogenic-leaning
SaProt	LLR -5.79	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.70	donor loss, 1 bp away · masked 0 · deltas
Pangolin	Δ0.58	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,710 alleles

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

Overall 0.000806% 13/1,613,670 alleles · very rare

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.Lys607Arg
Coding: c.1820A>G
MANE Select: NM_000124
dbSNP: rs200832611
Type: single nucleotide variant
Location: chr10:49493118 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 607: the helicase atp-binding domain; an α-helix

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

Disease context

Cockayne syndrome type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebrooculofacioskeletal syndrome 1 age related macular degeneration 5

For Cockayne syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ERCC6 p.Lys607Met 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-lys607arg (accessed [today's date]).

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