Is ERCC2 p.Ile456del (c.1361TCA[2]) pathogenic?

ERCC2 p.Ile456del (c.1361TCA[2]) is classified Pathogenic/Likely pathogenic in ERCC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-02-22). Very rare (popmax 0.004%, afr); Associated with xeroderma pigmentosum.

What condition is associated with ERCC2 p.Ile456del (c.1361TCA[2])?

ERCC2 p.Ile456del (c.1361TCA[2]) is associated with xeroderma pigmentosum, xeroderma pigmentosum group D, trichothiodystrophy 1, photosensitive (ClinVar).

How common is ERCC2 p.Ile456del (c.1361TCA[2]) in the general population?

ERCC2 p.Ile456del (c.1361TCA[2]) is very rare (popmax 0.004%, afr) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

ERCC2 p.Ile456del

c.1361TCA[2] · rs750123656 · VCV620626

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,926 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000434% 7/1,613,998 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,975
European (non-Finnish)	0.000339%	294,990

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.Ile456del
Coding: c.1361TCA[2]
MANE Select: NM_000400
dbSNP: rs750123656
Type: Microsatellite
Location: chr19:45357482 (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 456: a β-strand; the 'mediates interaction with mms19' region

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

Disease context

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

Also linked: xeroderma pigmentosum group D trichothiodystrophy 1, photosensitive cerebrooculofacioskeletal syndrome 2 craniopharyngioma

For Xeroderma pigmentosum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

ERCC2 c.184-1_186del Likely pathogenic ★★ same condition
ERCC2 p.Arg616fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Ile619del Pathogenic ★★ same condition
ERCC2 p.Ser630fs Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Ile456Thr Uncertain significance ★★ ⚠ same residue
ERCC2 p.Ile456Val Uncertain significance ★ ⚠ same residue
MAG p.Ser456Arg Uncertain significance ★ ⚠ same residue
ERCC2 c.106-5_142del 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-ile456del (accessed [today's date]).

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