Is ERCC2 p.Arg647Cys (c.1939C>T) pathogenic?

ERCC2 p.Arg647Cys (c.1939C>T) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-31). AlphaMissense: likely pathogenic (0.8661); Very rare (popmax 0.00878%, sas); Associated with Inborn genetic diseases.

What condition is associated with ERCC2 p.Arg647Cys (c.1939C>T)?

ERCC2 p.Arg647Cys (c.1939C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC2 p.Arg647Cys (c.1939C>T) in the general population?

ERCC2 p.Arg647Cys (c.1939C>T) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about ERCC2 p.Arg647Cys (c.1939C>T)?

AlphaMissense predicts likely pathogenic (score 0.8661) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg647Cys

c.1939C>T · rs370377312 · VCV1307820

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8661 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8661	likely pathogenic
REVEL	0.767	pathogenic-leaning
SaProt	LLR -14.16	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.78 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.4	GERP -2.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	26.0	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 0.00878% South Asian · 8/91,086 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00397% 64/1,613,846 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,386
East Asian	0.00446%	22,443
European (non-Finnish)	0.00407%	24,584
Remaining individualsnot grpmax-eligible	0.0032%	31,241
Finnishnot grpmax-eligible	0.00313%	31,917
Admixed American	0.00167%	59,990
African / African-American	0.00133%	74,932

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.Arg647Cys
Coding: c.1939C>T
MANE Select: NM_000400
dbSNP: rs370377312
Type: single nucleotide variant
Location: chr19:45352613 (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.Arg647Pro Uncertain significance ★ ⚠ same residue
ERCC2 p.Arg647= Likely benign ★ same residue
ERCC2 p.Arg647His Uncertain significance ★ ⚠ same residue
ERCC2 p.Arg647Leu 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

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-arg647cys (accessed [today's date]).

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