Is ERCC4 p.Phe186fs (c.557_558del) pathogenic?

ERCC4 p.Phe186fs (c.557558del) is classified Pathogenic/Likely pathogenic in ERCC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-21). Very rare (popmax 0.00134%, afr); Associated with Cockayne syndrome.

What condition is associated with ERCC4 p.Phe186fs (c.557_558del)?

ERCC4 p.Phe186fs (c.557_558del) is associated with Cockayne syndrome, xeroderma pigmentosum group F, Fanconi anemia complementation group Q (ClinVar).

How common is ERCC4 p.Phe186fs (c.557_558del) in the general population?

ERCC4 p.Phe186fs (c.557_558del) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Cockayne syndrome inherited?

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

ERCC4 p.Phe186fs

c.557_558del · rs1419167361 · VCV1400031

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

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 3 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,852 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,650 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,852
European (non-Finnish)	0.000339%	294,962

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.Phe186fs
Coding: c.557_558del
MANE Select: NM_005236
dbSNP: rs1419167361
Type: Deletion
Location: chr16:13926726 (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 186: the 'helicase-like' region

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

For Cockayne syndrome (Orphanet):

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

Similar variants

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.Thr495fs 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
ERCC4 p.Ile634fs 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-phe186fs (accessed [today's date]).

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