Is ERCC4 p.Arg415Gln (c.1244G>A) pathogenic?

ERCC4 p.Arg415Gln (c.1244G>A) is classified Benign/Likely benign in ERCC4 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.2055); Common (popmax 13.3%, mid) — too common for a highly-penetrant pathogenic allele; Associated with xeroderma pigmentosum group F.

What condition is associated with ERCC4 p.Arg415Gln (c.1244G>A)?

ERCC4 p.Arg415Gln (c.1244G>A) is associated with xeroderma pigmentosum group F, Fanconi anemia complementation group Q, Cockayne syndrome (ClinVar).

What do computational predictors say about ERCC4 p.Arg415Gln (c.1244G>A)?

AlphaMissense predicts likely benign (score 0.2055) — an in-silico prediction, not a clinical call.

ERCC4 p.Arg415Gln

Q: How common is ERCC4 p.Arg415Gln (c.1244G>A) in the general population?

ERCC4 p.Arg415Gln (c.1244G>A) is common (popmax 13.3%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

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

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

c.1244G>A · rs1800067 · VCV134155

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.2055 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 13.3%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

xeroderma pigmentosum group F

Computational evidence

Protein change
AlphaMissense	0.2055	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.3% Middle Eastern · 806/6,062 alleles

Filtering AF 12.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.2%

Overall 6.8% 109,649/1,613,408 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	13.3%	8
Ashkenazi Jewishnot grpmax-eligible	11.7%	9
European (non-Finnish)	7.7%	13
Remaining individualsnot grpmax-eligible	6.69%	15
Amishnot grpmax-eligible	5.59%	18
Admixed American	5.29%	19
South Asian	3.98%	25
Finnishnot grpmax-eligible	3.81%	26
African / African-American	1.45%	69
East Asian	0.0178%	5,611

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.Arg415Gln
Coding: c.1244G>A
MANE Select: NM_005236
dbSNP: rs1800067
Type: single nucleotide variant
Location: chr16:13935176 (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 415: the 'helicase-like' region; a UniProt-annotated variant site (in)

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.Arg415Gly 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-arg415gln (accessed [today's date]).

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