Is ERCC2 p.Cys116= (c.348T>C) pathogenic?

ERCC2 p.Cys116= (c.348T>C) is classified Conflicting classifications of pathogenicity in ERCC2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-08-17). Very rare (popmax 0.00153%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ERCC2 p.Cys116= (c.348T>C)?

ERCC2 p.Cys116= (c.348T>C) is associated with Inborn genetic diseases, xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 p.Cys116= (c.348T>C) in the general population?

ERCC2 p.Cys116= (c.348T>C) is very rare (popmax 0.00153%, nfe) (gnomAD).

ERCC2 p.Cys116=

c.348T>C · rs769231981 · VCV893796

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Conditions

Inborn genetic diseases

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 -0.54	GERP -3.3
Overall
CADD	6.203	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,177,542 alleles

Filtering AF 0.000955% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000788%

Overall 0.00143% 23/1,611,320 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00625%	16,011
Remaining individualsnot grpmax-eligible	0.0016%	62,346
European (non-Finnish)grpmax	0.00153%	65,419

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ERCC2
Protein: p.Cys116=
Coding: c.348T>C
MANE Select: NM_000400
dbSNP: rs769231981
Type: single nucleotide variant
Location: chr19:45368642 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 116: the helicase atp-binding domain; a binding site

Full ERCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group D

Similar variants

MAG p.Tyr116Phe Uncertain significance ★ ⚠ same residue
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1480-2A>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1666-2A>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1759-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.183+2T>A Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.361-1G>A Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.816-2A>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/ercc2-p-cys116 (accessed [today's date]).

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