Is ERCC2 p.Arg196Gln (c.587G>A) pathogenic?

ERCC2 p.Arg196Gln (c.587G>A) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-22). AlphaMissense: likely pathogenic (0.8821); Ultra-rare (popmax 0.0396%, sas).

How common is ERCC2 p.Arg196Gln (c.587G>A) in the general population?

ERCC2 p.Arg196Gln (c.587G>A) is ultra-rare (popmax 0.0396%, sas) (gnomAD).

What do computational predictors say about ERCC2 p.Arg196Gln (c.587G>A)?

AlphaMissense predicts likely pathogenic (score 0.8821) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg196Gln

c.587G>A · rs753293260 · VCV1305993

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8821 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0396%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8821	likely pathogenic
REVEL	0.798	moderately pathogenic-leaning
SaProt	LLR -12.73	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 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	32.0	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 0.0396% South Asian · 36/90,966 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.00255% 41/1,610,848 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0396%	2,527
Admixed American	0.00667%	15,002
European (non-Finnish)	8.49e-05%	1,177,178

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.Arg196Gln
Coding: c.587G>A
MANE Select: NM_000400
dbSNP: rs753293260
Type: single nucleotide variant
Location: chr19:45364845 (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 196: the helicase atp-binding domain; an α-helix

Full ERCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERCC2 p.Arg196Ter Pathogenic ★★ same residue
ERCC2 p.Arg196Pro Uncertain significance ★★ ⚠ same residue
ERCC2 p.Arg196_Tyr197insTer Pathogenic ★★ 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

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-arg196gln (accessed [today's date]).

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