Is ERCC2 p.Asn241Ser (c.722A>G) pathogenic?

ERCC2 p.Asn241Ser (c.722A>G) is classified Uncertain significance in ERCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-07). AlphaMissense: likely benign (0.0948); Very rare (popmax 0.00133%, afr).

How common is ERCC2 p.Asn241Ser (c.722A>G) in the general population?

ERCC2 p.Asn241Ser (c.722A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ERCC2 p.Asn241Ser (c.722A>G)?

AlphaMissense predicts likely benign (score 0.0948) — an in-silico prediction, not a clinical call.

ERCC2 p.Asn241Ser

c.722A>G · VCV4751520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0948 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0948	likely benign
REVEL	0.461	indeterminate
SaProt	LLR -10.10	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.79	acceptor gain · deltas
Pangolin	Δ0.27	gain · loss 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.1	GERP 1.8, 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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,008 alleles

Overall 6.84e-05% 1/1,461,680 alleles · very rare

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.Asn241Ser
Coding: c.722A>G
MANE Select: NM_000400
Type: single nucleotide variant
Location: chr19:45364328 (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 241: 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.Asn241= Likely benign ★★ same residue
ERCC2 p.Asn241Thr Uncertain significance ★ ⚠ same residue
MAG p.Val241Glu Uncertain significance ★ ⚠ same residue
MAG p.Val241Met Uncertain significance ★ ⚠ same residue
MAG p.Val241= Likely benign ★ same residue
MAG p.Val241fs Pathogenic ★ same residue
ERCC2 c.1238-1G>C Likely pathogenic ★★ same type
ERCC2 c.1308-2A>G 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-asn241ser (accessed [today's date]).

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