Is ERCC4 p.Arg292Gln (c.875G>A) pathogenic?

ERCC4 p.Arg292Gln (c.875G>A) is classified Uncertain significance in ERCC4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-14). AlphaMissense: likely benign (0.2202); Ultra-rare (popmax 0.0165%, mid); Associated with Fanconi anemia complementation group Q.

What condition is associated with ERCC4 p.Arg292Gln (c.875G>A)?

ERCC4 p.Arg292Gln (c.875G>A) is associated with Fanconi anemia complementation group Q, xeroderma pigmentosum group F, XFE progeroid syndrome (ClinVar).

How common is ERCC4 p.Arg292Gln (c.875G>A) in the general population?

ERCC4 p.Arg292Gln (c.875G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ERCC4 p.Arg292Gln (c.875G>A)?

AlphaMissense predicts likely benign (score 0.2202) — an in-silico prediction, not a clinical call.

ERCC4 p.Arg292Gln

c.875G>A · rs202243691 · VCV541248

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2202 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fanconi anemia complementation group Q

Computational evidence

Protein change
AlphaMissense	0.2202	likely benign
REVEL	0.728	pathogenic-leaning
SaProt	LLR -10.42	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.7, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	29.6	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00298% 48/1,611,440 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,785
Remaining individualsnot grpmax-eligible	0.00641%	15,594
European (non-Finnish)	0.00348%	28,726

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.Arg292Gln
Coding: c.875G>A
MANE Select: NM_005236
dbSNP: rs202243691
Type: single nucleotide variant
Location: chr16:13930792 (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 292: the 'helicase-like' region; the 'leucine-zipper 2' region

Full ERCC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Fanconi anemia complementation group Q — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group F XFE progeroid syndrome Cockayne syndrome

Similar variants

ERCC4 p.Arg292Ter Likely pathogenic ★ 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-arg292gln (accessed [today's date]).

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