Is ERCC4 p.Ile733= (c.2199C>T) pathogenic?

ERCC4 p.Ile733= (c.2199C>T) is classified Conflicting classifications of pathogenicity in ERCC4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-14). Ultra-rare (popmax 0.0231%, sas); Associated with xeroderma pigmentosum group F.

What condition is associated with ERCC4 p.Ile733= (c.2199C>T)?

ERCC4 p.Ile733= (c.2199C>T) is associated with xeroderma pigmentosum group F, Fanconi anemia complementation group Q, Cockayne syndrome (ClinVar).

How common is ERCC4 p.Ile733= (c.2199C>T) in the general population?

ERCC4 p.Ile733= (c.2199C>T) is ultra-rare (popmax 0.0231%, sas) (gnomAD).

ERCC4 p.Ile733=

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

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

c.2199C>T · rs372425414 · VCV317819

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, sas)

Conditions

xeroderma pigmentosum group F

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 -12	GERP -3.4
Overall
CADD	1.175	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0231% South Asian · 21/91,088 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.00173% 28/1,614,098 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0231%	4,338
Admixed American	0.005%	20,003
East Asian	0.00223%	44,896
European (non-Finnish)	0.000254%	393,343

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: ERCC4
Protein: p.Ile733=
Coding: c.2199C>T
MANE Select: NM_005236
dbSNP: rs372425414
Type: single nucleotide variant
Location: chr16:13947795 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.60 · 13 PDB
Residue 733: the ercc4 domain; the 'nuclease' region

Full ERCC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: Fanconi anemia complementation group Q Cockayne syndrome

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ERCC4 c.1102+1G>T Likely pathogenic ★★ same condition
ERCC4 c.793-2A>G Pathogenic ★★ same condition
ERCC4 p.Arg20Ter Pathogenic ★★ same condition
ERCC4 p.Arg589Trp Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Arg689Ser Likely pathogenic ★★ same condition
ERCC4 p.Arg772Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Cys236Arg Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Cys723Ter 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/ercc4-p-ile733 (accessed [today's date]).

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