Is ERCC2 p.Ala392Pro (c.1174G>C) pathogenic?

ERCC2 p.Ala392Pro (c.1174G>C) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-19). AlphaMissense: likely benign (0.2113); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ERCC2 p.Ala392Pro (c.1174G>C)?

ERCC2 p.Ala392Pro (c.1174G>C) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC2 p.Ala392Pro (c.1174G>C) in the general population?

ERCC2 p.Ala392Pro (c.1174G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERCC2 p.Ala392Pro (c.1174G>C)?

AlphaMissense predicts likely benign (score 0.2113) — an in-silico prediction, not a clinical call.

ERCC2 p.Ala392Pro

c.1174G>C · rs2123274630 · VCV1492513

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2113 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2113	likely benign
REVEL	0.242	benign-leaning
SaProt	LLR -10.00	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.8, phastCons 0.93
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	20.8	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.Ala392Pro
Coding: c.1174G>C
MANE Select: NM_000400
dbSNP: rs2123274630
Type: single nucleotide variant
Location: chr19:45361587 (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 392: an α-helix

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.Ala392= Likely benign ★ 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
ERCC2 p.Ala306Val Uncertain significance ★★ ⚠ same condition
ERCC2 p.Ala318Gly 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-ala392pro (accessed [today's date]).

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