Is ERCC2 p.Ser541Arg (c.1621A>C) pathogenic?

ERCC2 p.Ser541Arg (c.1621A>C) is classified Pathogenic in ERCC2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-07-24). AlphaMissense: likely pathogenic (0.9996); Ultra-rare (popmax 0.0134%, eas); Associated with xeroderma pigmentosum.

What condition is associated with ERCC2 p.Ser541Arg (c.1621A>C)?

ERCC2 p.Ser541Arg (c.1621A>C) is associated with xeroderma pigmentosum, xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 p.Ser541Arg (c.1621A>C) in the general population?

ERCC2 p.Ser541Arg (c.1621A>C) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

How is Xeroderma pigmentosum inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ERCC2 p.Ser541Arg (c.1621A>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

ERCC2 p.Ser541Arg

c.1621A>C · rs121913019 · VCV16783

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic ✓ concordant with ClinVar · top 2% in ERCC2
REVEL	0.964	strongly pathogenic-leaning
SaProt	LLR -14.44	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 7.8	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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,884 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000372% 6/1,614,106 alleles · ultra-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.Ser541Arg
Coding: c.1621A>C
MANE Select: NM_000400
dbSNP: rs121913019
Type: single nucleotide variant
Location: chr19:45354774 (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 541: the 'mediates interaction with mms19' region; a UniProt-annotated variant site (in xp-d; mild)

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

Disease context

xeroderma pigmentosum — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group D

For Xeroderma pigmentosum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

ERCC2 p.Ser541Asn Uncertain significance ★★ ⚠ same residue
ERCC2 p.Ser541Ile Uncertain significance ★ ⚠ same residue
ERCC2 p.Ser541= Likely benign ★ same residue
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1480-2A>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1666-2A>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1759-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.183+2T>A Pathogenic/Likely pathogenic ★★ 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-ser541arg (accessed [today's date]).

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