Is ERCC4 p.Ala596= (c.1788G>A) pathogenic?

ERCC4 p.Ala596= (c.1788G>A) is classified Likely benign in ERCC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). Very rare (popmax 0.0011%, sas); Associated with Cockayne syndrome.

What condition is associated with ERCC4 p.Ala596= (c.1788G>A)?

ERCC4 p.Ala596= (c.1788G>A) is associated with Cockayne syndrome, xeroderma pigmentosum group F, Fanconi anemia complementation group Q (ClinVar).

How common is ERCC4 p.Ala596= (c.1788G>A) in the general population?

ERCC4 p.Ala596= (c.1788G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Cockayne syndrome inherited?

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

ERCC4 p.Ala596=

c.1788G>A · rs374303503 · VCV1642496

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Cockayne syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	donor loss · deltas
Constraint at this position
Conservation	phyloP -3.5	GERP -3.1
Overall
CADD	1.172	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,074 alleles

Overall 0.000205% 3/1,461,472 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,480
South Asiangrpmax	0.0011%	91,074
European (non-Finnish)	8.48e-05%	1,179,651

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala596=
Coding: c.1788G>A
MANE Select: NM_005236
dbSNP: rs374303503
Type: single nucleotide variant
Location: chr16:13935720 (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

For Cockayne syndrome (Orphanet):

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

Similar variants

ERCC4 p.Ala596Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
ERCC4 p.Ala596Val Uncertain significance ★ ⚠ same residue
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

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-ala596 (accessed [today's date]).

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