Is ERCC2 p.Met1Val (c.1A>G) pathogenic?

ERCC2 p.Met1Val (c.1A>G) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-15). Ultra-rare (popmax 0.0367%, mid).

How common is ERCC2 p.Met1Val (c.1A>G) in the general population?

ERCC2 p.Met1Val (c.1A>G) is ultra-rare (popmax 0.0367%, mid) (gnomAD).

ERCC2 p.Met1Val

c.1A>G · rs757252017 · VCV1683246

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, mid)

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	0.62	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.8, phastCons 1
Overall
CADD	23.3	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 0.0367% Middle Eastern · 2/5,448 alleles

Filtering AF 0.00642% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00264%

Overall 0.000991% 15/1,512,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0367%	2,724
Ashkenazi Jewishnot grpmax-eligible	0.00382%	26,148
Remaining individualsnot grpmax-eligible	0.00178%	56,212
European (non-Finnish)	0.000979%	102,155

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.Met1Val
Coding: c.1A>G
MANE Select: NM_000400
dbSNP: rs757252017
Type: single nucleotide variant
Location: chr19:45370540 (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.Met1Arg 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-met1val (accessed [today's date]).

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