Is ERCC5 p.His46= (c.138T>C) pathogenic?

ERCC5 p.His46= (c.138T>C) is classified Benign/Likely benign in ERCC5 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 66.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with xeroderma pigmentosum group G.

What condition is associated with ERCC5 p.His46= (c.138T>C)?

ERCC5 p.His46= (c.138T>C) is associated with xeroderma pigmentosum group G (ClinVar).

ERCC5 p.His46=

Q: How common is ERCC5 p.His46= (c.138T>C) in the general population?

ERCC5 p.His46= (c.138T>C) is common (popmax 66.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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

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

c.138T>C · rs1047768 · VCV129009

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 66.7%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

xeroderma pigmentosum group G

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -4	GERP -4.6
Overall
CADD	0.104	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 66.7% African / African-American · 49,935/74,920 alleles

Filtering AF 66.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 66%

Overall 57.5% 927,804/1,613,696 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	66.7%	2
Finnishnot grpmax-eligible	61.5%	2
European (non-Finnish)	59.9%	2
Amishnot grpmax-eligible	58.1%	2
Ashkenazi Jewishnot grpmax-eligible	57.8%	2
Remaining individualsnot grpmax-eligible	56.6%	2
Middle Eastern	52.1%	2
South Asian	50.1%	2
Admixed American	33.9%	3
East Asian	22.7%	4

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: ERCC5
Protein: p.His46=
Coding: c.138T>C
dbSNP: rs1047768
Type: single nucleotide variant
Location: chr13:102852167 (GRCh38)

Full ERCC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

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/ercc5-p-his46 (accessed [today's date]).

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