Is ERCC6 p.Ser797Cys (c.2390C>G) pathogenic?

ERCC6 p.Ser797Cys (c.2390C>G) is classified Conflicting classifications of pathogenicity in ERCC6 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.1005); Rare (popmax 0.196%, nfe); Associated with Cockayne syndrome type 2.

What condition is associated with ERCC6 p.Ser797Cys (c.2390C>G)?

ERCC6 p.Ser797Cys (c.2390C>G) is associated with Cockayne syndrome type 2, intellectual disability, cerebrooculofacioskeletal syndrome 1 (ClinVar).

How common is ERCC6 p.Ser797Cys (c.2390C>G) in the general population?

ERCC6 p.Ser797Cys (c.2390C>G) is rare (popmax 0.196%, 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.Ser797Cys (c.2390C>G)?

AlphaMissense predicts likely benign (score 0.1005) — an in-silico prediction, not a clinical call.

ERCC6 p.Ser797Cys

c.2390C>G · rs146043988 · VCV300067

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1005 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.196%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cockayne syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.1005	likely benign
REVEL	0.484	indeterminate
SaProt	LLR -11.95	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	26.8	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 0.196% European (non-Finnish) · 2,312/1,179,564 alleles

Filtering AF 0.189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.187%

Overall 0.151% 2,443/1,613,602 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.196%	510
Remaining individualsnot grpmax-eligible	0.109%	919
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,691
Admixed American	0.0317%	3,159
African / African-American	0.0187%	5,359
Middle Eastern	0.0165%	6,060
South Asian	0.0154%	6,505
Finnishnot grpmax-eligible	0.00625%	15,998

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.Ser797Cys
Coding: c.2390C>G
MANE Select: NM_000124
dbSNP: rs146043988
Type: single nucleotide variant
Location: chr10:49474235 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 797: 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: intellectual disability 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.Ser797= Conflicting classifications of pathogenicity ★ same residue
ERCC6 p.Ala797= 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

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-ser797cys (accessed [today's date]).

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