Is ERCC2 p.Ala550Val (c.1649C>T) pathogenic?

ERCC2 p.Ala550Val (c.1649C>T) is classified Uncertain significance in ERCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely pathogenic (0.7613); Very rare (popmax 0.000932%, nfe); Associated with xeroderma pigmentosum group D.

What condition is associated with ERCC2 p.Ala550Val (c.1649C>T)?

ERCC2 p.Ala550Val (c.1649C>T) is associated with xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 p.Ala550Val (c.1649C>T) in the general population?

ERCC2 p.Ala550Val (c.1649C>T) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about ERCC2 p.Ala550Val (c.1649C>T)?

AlphaMissense predicts likely pathogenic (score 0.7613) — an in-silico prediction, not a clinical call.

ERCC2 p.Ala550Val

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

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

c.1649C>T · rs886054496 · VCV329509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum group D

Computational evidence

Protein change
AlphaMissense	0.7613	likely pathogenic
REVEL	0.703	pathogenic-leaning
SaProt	LLR -9.04	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	26.8	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 0.000932% European (non-Finnish) · 11/1,179,954 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000753% 11/1,461,726 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.Ala550Val
Coding: c.1649C>T
MANE Select: NM_000400
dbSNP: rs886054496
Type: single nucleotide variant
Location: chr19:45354746 (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 550: an α-helix; the 'mediates interaction with mms19' region

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.Ala550= 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
ERCC2 c.816-2A>G 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-ala550val (accessed [today's date]).

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