Is ERCC3 p.Thr445= (c.1335C>T) pathogenic?

ERCC3 p.Thr445= (c.1335C>T) is classified Benign/Likely benign in ERCC3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Low-frequency (popmax 1.44%, afr); Associated with xeroderma pigmentosum group B.

What condition is associated with ERCC3 p.Thr445= (c.1335C>T)?

ERCC3 p.Thr445= (c.1335C>T) is associated with xeroderma pigmentosum group B (ClinVar).

How common is ERCC3 p.Thr445= (c.1335C>T) in the general population?

ERCC3 p.Thr445= (c.1335C>T) is low-frequency (popmax 1.44%, afr) (gnomAD).

ERCC3 p.Thr445=

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

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

c.1335C>T · rs4150422 · VCV783340

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.44%, afr)

Conditions

xeroderma pigmentosum group B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP -4.3, phastCons 0.96
Overall
CADD	4.767	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.44% African / African-American · 1,076/74,972 alleles

Filtering AF 1.36% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.34%

Overall 0.0826% 1,333/1,613,726 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.44%	70
Middle Eastern	0.116%	865
Remaining individualsnot grpmax-eligible	0.102%	976
Admixed American	0.09%	1,111
European (non-Finnish)	0.0108%	9,290
South Asian	0.00549%	18,215

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.Thr445=
Coding: c.1335C>T
MANE Select: NM_000122
dbSNP: rs4150422
Type: single nucleotide variant
Location: chr2:127286710 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 445: the helicase atp-binding domain; an α-helix

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.Thr445Ala Uncertain significance ★ ⚠ same residue
ERCC3 p.Thr445Ser Uncertain significance ★ ⚠ 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

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-thr445 (accessed [today's date]).

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