Is ERCC4 p.Ile746fs (c.2236_2243delinsTGTACA) pathogenic?

ERCC4 p.Ile746fs (c.22362243delinsTGTACA) is classified Likely pathogenic in ERCC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-14). Associated with XFE progeroid syndrome.

What condition is associated with ERCC4 p.Ile746fs (c.2236_2243delinsTGTACA)?

ERCC4 p.Ile746fs (c.2236_2243delinsTGTACA) is associated with XFE progeroid syndrome, xeroderma pigmentosum group F, Fanconi anemia complementation group Q (ClinVar).

ERCC4 p.Ile746fs

c.2236_2243delinsTGTACA · VCV3578448

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

XFE progeroid syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (11 of 11) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.1	GERP -3.4

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: ERCC4
Protein: p.Ile746fs
Coding: c.2236_2243delinsTGTACA
MANE Select: NM_005236
Type: Indel
Location: chr16:13947832 (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 746: the ercc4 domain; the 'nuclease' region

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

Disease context

XFE progeroid syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group F Fanconi anemia complementation group Q

Similar variants

ERCC4 p.Ile746Val Conflicting classifications of pathogenicity ★ ⚠ same residue
ERCC4 p.Ala638Leu Uncertain significance ★ same condition
ERCC4 p.Ile746Met Uncertain significance ★ ⚠ same residue
ERCC4 p.Val642Phe Uncertain significance ★ same condition
ERCC4 c.1102+1G>T Likely pathogenic ★★ same condition
ERCC4 c.793-2A>G Pathogenic ★★ same condition
ERCC4 p.Ala400fs Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Arg20Ter 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-ile746fs (accessed [today's date]).

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