Is ERCC2 p.Thr709Ala (c.2125A>G) pathogenic?

ERCC2 p.Thr709Ala (c.2125A>G) is classified Uncertain significance in ERCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-10). AlphaMissense: ambiguous (0.5129); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ERCC2 p.Thr709Ala (c.2125A>G)?

ERCC2 p.Thr709Ala (c.2125A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC2 p.Thr709Ala (c.2125A>G) in the general population?

ERCC2 p.Thr709Ala (c.2125A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERCC2 p.Thr709Ala (c.2125A>G)?

AlphaMissense predicts ambiguous (score 0.5129) — an in-silico prediction, not a clinical call.

ERCC2 p.Thr709Ala

c.2125A>G · VCV3276273

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5129 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5129	ambiguous
REVEL	0.627	indeterminate
SaProt	LLR -8.26	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ERCC2
Protein: p.Thr709Ala
Coding: c.2125A>G
MANE Select: NM_000400
Type: single nucleotide variant
Location: chr19:45352274 (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

Disease context

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

Similar variants

ERCC2 p.Thr709= Likely benign ★★ same residue
ERCC2 p.Thr709Ile Uncertain significance ★ ⚠ same residue
ERCC2 p.Thr709Pro Likely pathogenic ★★ ⚠ 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-thr709ala (accessed [today's date]).

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