Is ERCC2 p.Lys718= (c.2154G>A) pathogenic?

ERCC2 p.Lys718= (c.2154G>A) is classified Likely benign in ERCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-09). Very rare (popmax 6.2e-05%); Associated with Inborn genetic diseases.

What condition is associated with ERCC2 p.Lys718= (c.2154G>A)?

ERCC2 p.Lys718= (c.2154G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC2 p.Lys718= (c.2154G>A) in the general population?

ERCC2 p.Lys718= (c.2154G>A) is very rare (popmax 6.2e-05%) (gnomAD).

ERCC2 p.Lys718=

c.2154G>A · VCV3509838

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

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 4.8	GERP 1.6, phastCons 1
Overall
CADD	12.33	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,614,108 alleles · very rare exomes 1/1,461,794 · genomes 0/152,314 · joint denominator

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.Lys718=
Coding: c.2154G>A
MANE Select: NM_000400
Type: single nucleotide variant
Location: chr19:45352245 (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 718: an α-helix; a UniProt-annotated variant site (in xp-d and ttd1; no longer interacts with gtf2h2/p44; has 5'-3' helicase activity)

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

Similar variants

ERCC2 p.Lys718Gln Uncertain significance ★ ⚠ same residue
ERCC2 p.Lys718Glu Uncertain significance ★ ⚠ same residue
ERCC2 p.Lys718Met Uncertain significance ★ ⚠ same residue
ERCC2 p.Ala725Pro Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Arg616Pro Pathogenic ★★ same condition
ERCC2 p.Ala108Thr Uncertain significance ★★ ⚠ same condition
ERCC2 p.Ala144Val Uncertain significance ★★ ⚠ same condition
ERCC2 p.Ala226Thr Uncertain significance ★★ ⚠ 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-lys718 (accessed [today's date]).

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