Is ERCC2 p.Leu485Pro (c.1454T>C) pathogenic?

ERCC2 p.Leu485Pro (c.1454T>C) is classified Pathogenic in ERCC2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2001-10-15). AlphaMissense: likely pathogenic (0.9892); Very rare (popmax 0.000254%, nfe); Associated with xeroderma pigmentosum group D.

What condition is associated with ERCC2 p.Leu485Pro (c.1454T>C)?

ERCC2 p.Leu485Pro (c.1454T>C) is associated with xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 p.Leu485Pro (c.1454T>C) in the general population?

ERCC2 p.Leu485Pro (c.1454T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ERCC2 p.Leu485Pro (c.1454T>C)?

AlphaMissense predicts likely pathogenic (score 0.9892) — an in-silico prediction, not a clinical call.

ERCC2 p.Leu485Pro

Q: How is Xeroderma pigmentosum-Cockayne syndrome complex inherited?

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

c.1454T>C · rs121913025 · VCV16791

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9892 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum group D

Computational evidence

Protein change
AlphaMissense	0.9892	likely pathogenic ✓ concordant with ClinVar
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -11.90	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 1.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	26.1	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 0.000254% European (non-Finnish) · 3/1,179,830 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,634 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,496
European (non-Finnish)grpmax	0.000254%	393,277

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu485Pro
Coding: c.1454T>C
MANE Select: NM_000400
dbSNP: rs121913025
Type: single nucleotide variant
Location: chr19:45357295 (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 485: the 'mediates interaction with mms19' region; a UniProt-annotated variant site (in xp-d; the corresponding mutation in fission yeast causes complete loss of activity)

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

Disease context

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

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ERCC2 p.Leu485Val Uncertain significance ★ ⚠ same residue
ERCC2 p.Leu485= 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
ERCC2 c.361-1G>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-leu485pro (accessed [today's date]).

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