Is ERCC8 p.Gln228= (c.684A>G) pathogenic?

ERCC8 p.Gln228= (c.684A>G) is classified Likely benign in ERCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-20). Ultra-rare (popmax 0.0417%, sas).

How common is ERCC8 p.Gln228= (c.684A>G) in the general population?

ERCC8 p.Gln228= (c.684A>G) is ultra-rare (popmax 0.0417%, sas) (gnomAD).

ERCC8 p.Gln228=

c.684A>G · rs766516991 · VCV2906474

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -3.1, phastCons 0.94
Overall
CADD	5.62	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0417% South Asian · 38/91,056 alleles

Filtering AF 0.0312% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0276%

Overall 0.00242% 39/1,612,240 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0417%	2,396
Remaining individualsnot grpmax-eligible	0.0016%	62,430

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.Gln228=
Coding: c.684A>G
MANE Select: NM_000082
dbSNP: rs766516991
Type: single nucleotide variant
Location: chr5:60899661 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 16 PDB
Residue 228: a β-strand

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

Similar variants

ERCC8 p.Gln228Glu Uncertain significance ★ ⚠ same residue
ERCC8 p.Gln228His Uncertain significance ★ ⚠ same residue
ERCC8 p.Gln228Pro Uncertain significance ★ ⚠ 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

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-gln228 (accessed [today's date]).

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