Is ERCC4 p.Arg726= (c.2178C>T) pathogenic?

ERCC4 p.Arg726= (c.2178C>T) is classified Conflicting classifications of pathogenicity in ERCC4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-04). Ultra-rare (popmax 0.0165%, mid); Associated with Fanconi anemia complementation group Q.

What condition is associated with ERCC4 p.Arg726= (c.2178C>T)?

ERCC4 p.Arg726= (c.2178C>T) is associated with Fanconi anemia complementation group Q, xeroderma pigmentosum group F, Cockayne syndrome (ClinVar).

How common is ERCC4 p.Arg726= (c.2178C>T) in the general population?

ERCC4 p.Arg726= (c.2178C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

ERCC4 p.Arg726=

c.2178C>T · rs1255618541 · VCV888106

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Fanconi anemia complementation group Q

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 0.91	GERP 0.74, phastCons 1
Overall
CADD	11.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,461,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.000339%	295,009

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.Arg726=
Coding: c.2178C>T
MANE Select: NM_005236
dbSNP: rs1255618541
Type: single nucleotide variant
Location: chr16:13947774 (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 726: the ercc4 domain; the 'nuclease' 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 Cockayne syndrome

Similar variants

ERCC4 p.Arg726Cys Uncertain significance ★ ⚠ same residue
ERCC4 p.Arg726His 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-arg726 (accessed [today's date]).

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