Is ERCC4 p.Glu141Lys (c.421G>A) pathogenic?

ERCC4 p.Glu141Lys (c.421G>A) is classified Uncertain significance in ERCC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-12). AlphaMissense: likely pathogenic (0.6045); Ultra-rare (popmax 0.0329%, mid); Associated with xeroderma pigmentosum group F.

What condition is associated with ERCC4 p.Glu141Lys (c.421G>A)?

ERCC4 p.Glu141Lys (c.421G>A) is associated with xeroderma pigmentosum group F, Fanconi anemia complementation group Q, Cockayne syndrome (ClinVar).

How common is ERCC4 p.Glu141Lys (c.421G>A) in the general population?

ERCC4 p.Glu141Lys (c.421G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about ERCC4 p.Glu141Lys (c.421G>A)?

AlphaMissense predicts likely pathogenic (score 0.6045) — an in-silico prediction, not a clinical call.

ERCC4 p.Glu141Lys

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

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

c.421G>A · rs760865964 · VCV2930494

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6045 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

xeroderma pigmentosum group F

Computational evidence

Protein change
AlphaMissense	0.6045	likely pathogenic
REVEL	0.523	indeterminate
SaProt	LLR -13.36	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000929% 15/1,613,966 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
East Asian	0.00446%	22,442
European (non-Finnish)	0.000932%	107,274

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.Glu141Lys
Coding: c.421G>A
MANE Select: NM_005236
dbSNP: rs760865964
Type: single nucleotide variant
Location: chr16:13926593 (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 141: 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 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
ERCC4 p.Cys723Ter 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-glu141lys (accessed [today's date]).

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