Is ERCC4 p.Thr495fs (c.1484_1488del) pathogenic?

ERCC4 p.Thr495fs (c.14841488del) is classified Pathogenic in ERCC4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-12). Very rare (popmax 0.00195%, nfe); Associated with Cockayne syndrome.

What condition is associated with ERCC4 p.Thr495fs (c.1484_1488del)?

ERCC4 p.Thr495fs (c.1484_1488del) is associated with Cockayne syndrome, xeroderma pigmentosum group F, Fanconi anemia complementation group Q (ClinVar).

How common is ERCC4 p.Thr495fs (c.1484_1488del) in the general population?

ERCC4 p.Thr495fs (c.1484_1488del) is very rare (popmax 0.00195%, nfe) (gnomAD).

How is Cockayne syndrome inherited?

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

ERCC4 p.Thr495fs

c.1484_1488del · rs397509400 · VCV55823

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Conditions

Cockayne 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	predicted	premature termination codon in exon 8 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.1	GERP 1.5, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00195% European (non-Finnish) · 23/1,179,766 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00171% 25/1,460,740 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,294
Admixed American	0.00167%	59,806
South Asian	0.0011%	90,654

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.Thr495fs
Coding: c.1484_1488del
MANE Select: NM_005236
dbSNP: rs397509400
Type: Deletion
Location: chr16:13935414 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.60 · 13 PDB

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

Disease context

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

Also linked: xeroderma pigmentosum group F Fanconi anemia complementation group Q precursor B-cell acute lymphoblastic leukemia

For Cockayne syndrome (Orphanet):

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

Similar variants

ERCC4 p.Thr495Ile Uncertain significance ★ ⚠ same residue
ERCC4 p.Arg468fs Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Asn308fs Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Glu628fs Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Phe186fs Pathogenic/Likely pathogenic ★★ same condition
ERCC4 c.1905-8_1909del Likely pathogenic ★ same condition
ERCC4 p.Ala13fs Likely pathogenic ★ same condition
ERCC4 p.Arg576_Tyr577insTer 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-thr495fs (accessed [today's date]).

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