Is ERCC8 p.Cys356Ter (c.1068C>A) pathogenic?

ERCC8 p.Cys356Ter (c.1068C>A) is classified Pathogenic in ERCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). Very rare (popmax 0.00627%, nfe).

How common is ERCC8 p.Cys356Ter (c.1068C>A) in the general population?

ERCC8 p.Cys356Ter (c.1068C>A) is very rare (popmax 0.00627%, nfe) (gnomAD).

ERCC8 p.Cys356Ter

c.1068C>A · rs141898557 · VCV934772

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00627%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 12
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 1.1, phastCons 1
Overall
CADD	36.0	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 0.00627% European (non-Finnish) · 74/1,179,824 alleles

Filtering AF 0.00511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00465% 75/1,613,766 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00627%	15,944
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: ERCC8
Protein: p.Cys356Ter
Coding: c.1068C>A
MANE Select: NM_000082
dbSNP: rs141898557
Type: single nucleotide variant
Location: chr5:60887494 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 16 PDB
Residue 356: a UniProt-annotated variant site (in csa); a turn

Full ERCC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERCC8 p.Cys356= Likely benign ★ same residue
ERCC8 c.1041+1G>T Pathogenic/Likely pathogenic ★★ same type
ERCC8 c.1042-2A>G Pathogenic/Likely pathogenic ★★ same type
ERCC8 c.173+1119G>C Pathogenic/Likely pathogenic ★★ same type
ERCC8 c.173+1G>A Pathogenic/Likely pathogenic ★★ same type
ERCC8 c.275+1G>A Pathogenic ★★ same type
ERCC8 c.276-1G>A Likely pathogenic ★★ same type
ERCC8 c.399+1G>A Likely pathogenic ★★ same type

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/ercc8-p-cys356ter (accessed [today's date]).

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