Is ERCC2 p.Met1Arg (c.2T>G) pathogenic?

ERCC2 p.Met1Arg (c.2T>G) is classified Uncertain significance in ERCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). Very rare (popmax 8.55e-05%, nfe).

How common is ERCC2 p.Met1Arg (c.2T>G) in the general population?

ERCC2 p.Met1Arg (c.2T>G) is very rare (popmax 8.55e-05%, nfe) (gnomAD).

ERCC2 p.Met1Arg

c.2T>G · VCV3389398

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.55e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.723	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.8, phastCons 1
Overall
CADD	24.5	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 8.55e-05% European (non-Finnish) · 1/1,170,238 alleles

Overall 0.000139% 2/1,435,556 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00345%	28,998
European (non-Finnish)grpmax	8.55e-05%	1,170,238

Ashkenazi Jewish 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.Met1Arg
Coding: c.2T>G
MANE Select: NM_000400
Type: single nucleotide variant
Location: chr19:45370539 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB

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

Similar variants

ERCC2 p.Met1Val Uncertain significance ★★ same residue
ERCC2 p.Met1Thr Uncertain significance ★ same residue
ERCC2 c.1238-1G>C Likely pathogenic ★★ same type
ERCC2 c.1308-2A>G Likely pathogenic ★★ same type
ERCC2 c.1378-1G>T Pathogenic/Likely pathogenic ★★ same type
ERCC2 c.1479+2T>C Pathogenic/Likely pathogenic ★★ same type
ERCC2 c.1480-1G>C Pathogenic/Likely pathogenic ★★ same type
ERCC2 c.1480-2A>C Pathogenic/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/ercc2-p-met1arg (accessed [today's date]).

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