Is ERCC3 p.Arg360Cys (c.1078C>T) pathogenic?

ERCC3 p.Arg360Cys (c.1078C>T) is classified Uncertain significance in ERCC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-01). AlphaMissense: likely pathogenic (0.8212); Ultra-rare (popmax 0.0254%, afr); Associated with xeroderma pigmentosum group B.

What condition is associated with ERCC3 p.Arg360Cys (c.1078C>T)?

ERCC3 p.Arg360Cys (c.1078C>T) is associated with xeroderma pigmentosum group B (ClinVar).

How common is ERCC3 p.Arg360Cys (c.1078C>T) in the general population?

ERCC3 p.Arg360Cys (c.1078C>T) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

What do computational predictors say about ERCC3 p.Arg360Cys (c.1078C>T)?

AlphaMissense predicts likely pathogenic (score 0.8212) — an in-silico prediction, not a clinical call.

ERCC3 p.Arg360Cys

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

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

c.1078C>T · rs754010782 · VCV331084

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8212 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

xeroderma pigmentosum group B

Computational evidence

Protein change
AlphaMissense	0.8212	likely pathogenic
REVEL	0.364	indeterminate
SaProt	LLR -12.92	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	33.0	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 0.0254% African / African-American · 19/74,916 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00465% 75/1,613,864 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,943
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)	0.00415%	24,082
East Asian	0.00223%	44,894
Admixed American	0.00167%	60,002

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: ERCC3
Protein: p.Arg360Cys
Coding: c.1078C>T
MANE Select: NM_000122
dbSNP: rs754010782
Type: single nucleotide variant
Location: chr2:127286967 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 360: the helicase atp-binding domain

Full ERCC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

xeroderma pigmentosum group B — 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

ERCC3 p.Arg360His Conflicting classifications of pathogenicity ★ ⚠ same residue
ERCC3 c.1828-1G>C Likely pathogenic ★★ same condition
ERCC3 c.471+1G>A Pathogenic ★★ same condition
ERCC3 c.657+1G>A Likely pathogenic ★★ same condition
ERCC3 p.Arg109Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Arg195Ter Pathogenic ★★ same condition
ERCC3 p.Arg425Ter Pathogenic ★★ same condition
ERCC3 p.Arg452Ter 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/ercc3-p-arg360cys (accessed [today's date]).

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