Is ERCC6 p.Ser674= (c.2022T>A) pathogenic?

ERCC6 p.Ser674= (c.2022T>A) is classified Conflicting classifications of pathogenicity in ERCC6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.0604%, sas); Associated with cerebrooculofacioskeletal syndrome 1.

What condition is associated with ERCC6 p.Ser674= (c.2022T>A)?

ERCC6 p.Ser674= (c.2022T>A) is associated with cerebrooculofacioskeletal syndrome 1, age related macular degeneration 5, Cockayne syndrome type 2 (ClinVar).

How common is ERCC6 p.Ser674= (c.2022T>A) in the general population?

ERCC6 p.Ser674= (c.2022T>A) is ultra-rare (popmax 0.0604%, sas) (gnomAD).

ERCC6 p.Ser674=

c.2022T>A · rs544471829 · VCV300074

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0604%, sas)

Conditions

cerebrooculofacioskeletal syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.1	GERP -5.1
Overall
CADD	5.521	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0604% South Asian · 55/91,076 alleles

Filtering AF 0.0476% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.043%

Overall 0.00589% 95/1,614,194 alleles · ultra-rare exomes 91/1,461,870 · genomes 4/152,324 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0604%	1,656
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.016%	6,251
Admixed American	0.00666%	15,006
European (non-Finnish)	0.00195%	51,305

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.Ser674=
Coding: c.2022T>A
MANE Select: NM_000124
dbSNP: rs544471829
Type: single nucleotide variant
Location: chr10:49482834 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 674: the helicase atp-binding domain

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 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-ser674 (accessed [today's date]).

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