Is ERCC6 p.Arg652Ter (c.1954C>T) pathogenic?

ERCC6 p.Arg652Ter (c.1954C>T) is classified Pathogenic/Likely pathogenic in ERCC6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-21). Very rare (popmax 0.00373%, nfe); Associated with Cockayne syndrome.

What condition is associated with ERCC6 p.Arg652Ter (c.1954C>T)?

ERCC6 p.Arg652Ter (c.1954C>T) is associated with Cockayne syndrome, cerebrooculofacioskeletal syndrome 1, de Sanctis-Cacchione syndrome (ClinVar).

How common is ERCC6 p.Arg652Ter (c.1954C>T) in the general population?

ERCC6 p.Arg652Ter (c.1954C>T) is very rare (popmax 0.00373%, nfe) (gnomAD).

How is Cockayne syndrome inherited?

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

ERCC6 p.Arg652Ter

c.1954C>T · rs767247987 · VCV190155

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Conditions

Cockayne syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 21
Splicing
SpliceAI	Δ0.34	donor gain, 44 bp away · masked 0 · deltas
Pangolin	Δ0.30	gain · loss 0.18 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.9	GERP 0.76, phastCons 1
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00373% European (non-Finnish) · 44/1,180,008 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00308% 45/1,461,830 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00373%	26,818
South Asian	0.0011%	91,078

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.Arg652Ter
Coding: c.1954C>T
MANE Select: NM_000124
dbSNP: rs767247987
Type: single nucleotide variant
Location: chr10:49483384 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 652: the helicase atp-binding domain; a UniProt-annotated variant site (in a colorectal cancer sample; somatic mutation)

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

Disease context

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

Also linked: cerebrooculofacioskeletal syndrome 1 de Sanctis-Cacchione syndrome Cockayne syndrome type 2

For Cockayne syndrome (Orphanet):

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

Similar variants

ERCC6 p.Arg652Gln Uncertain significance ★ ⚠ same residue
ERCC6 p.Arg652= 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-arg652ter (accessed [today's date]).

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