Is ERCC2 p.Arg324Cys (c.970C>T) pathogenic?

ERCC2 p.Arg324Cys (c.970C>T) is classified Uncertain significance in ERCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-23). AlphaMissense: likely pathogenic (0.9118); Very rare (popmax 0.00118%, sas); Associated with Inborn genetic diseases.

What condition is associated with ERCC2 p.Arg324Cys (c.970C>T)?

ERCC2 p.Arg324Cys (c.970C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC2 p.Arg324Cys (c.970C>T) in the general population?

ERCC2 p.Arg324Cys (c.970C>T) is very rare (popmax 0.00118%, sas) (gnomAD).

What do computational predictors say about ERCC2 p.Arg324Cys (c.970C>T)?

AlphaMissense predicts likely pathogenic (score 0.9118) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg324Cys

c.970C>T · rs1322620921 · VCV2447127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9118 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00118%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9118	likely pathogenic
REVEL	0.966	strongly pathogenic-leaning
SaProt	LLR -14.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00118% South Asian · 1/85,084 alleles

Filtering AF 8.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.000323% 5/1,549,046 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00118%	85,084
European (non-Finnish)	0.000347%	288,558

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.Arg324Cys
Coding: c.970C>T
MANE Select: NM_000400
dbSNP: rs1322620921
Type: single nucleotide variant
Location: chr19:45363891 (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 324: a β-strand

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.Arg324His Uncertain significance ★★ ⚠ same residue
ERCC2 p.Arg324= Likely benign ★★ same residue
ERCC2 p.Arg324Pro 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-arg324cys (accessed [today's date]).

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