Is ERCC4 p.Ala11= (c.33C>T) pathogenic?

ERCC4 p.Ala11= (c.33C>T) is classified Benign/Likely benign in ERCC4 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-02). Low-frequency (popmax 2.49%, nfe); Associated with xeroderma pigmentosum group F.

What condition is associated with ERCC4 p.Ala11= (c.33C>T)?

ERCC4 p.Ala11= (c.33C>T) is associated with xeroderma pigmentosum group F, Fanconi anemia complementation group Q, Cockayne syndrome (ClinVar).

How common is ERCC4 p.Ala11= (c.33C>T) in the general population?

ERCC4 p.Ala11= (c.33C>T) is low-frequency (popmax 2.49%, nfe) (gnomAD).

ERCC4 p.Ala11=

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

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

c.33C>T · rs3136042 · VCV240125

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.49%, nfe)

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 -6.5	GERP -3.7
Overall
CADD	3.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.49% European (non-Finnish) · 29,346/1,179,900 alleles

Filtering AF 2.46% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.45%

Overall 1.99% 32,024/1,607,076 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	2.49%	40
Amishnot grpmax-eligible	1.54%	65
Remaining individualsnot grpmax-eligible	1.52%	66
Finnishnot grpmax-eligible	1.02%	98
Ashkenazi Jewishnot grpmax-eligible	0.845%	118
Admixed American	0.541%	185
African / African-American	0.513%	195
South Asian	0.18%	555
Middle Eastern	0.116%	860

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.Ala11=
Coding: c.33C>T
MANE Select: NM_005236
dbSNP: rs3136042
Type: single nucleotide variant
Location: chr16:13920198 (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 11: the 'helicase-like' 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 p.Ala11Val 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
ERCC4 p.Cys236Arg 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-ala11 (accessed [today's date]).

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