Is ERCC4 p.Arg87His (c.260G>A) pathogenic?

ERCC4 p.Arg87His (c.260G>A) is classified Uncertain significance in ERCC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-08). AlphaMissense: likely benign (0.1766); Ultra-rare (popmax 0.015%, amr); Associated with xeroderma pigmentosum group F.

What condition is associated with ERCC4 p.Arg87His (c.260G>A)?

ERCC4 p.Arg87His (c.260G>A) is associated with xeroderma pigmentosum group F, Fanconi anemia complementation group Q, Cockayne syndrome (ClinVar).

How common is ERCC4 p.Arg87His (c.260G>A) in the general population?

ERCC4 p.Arg87His (c.260G>A) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about ERCC4 p.Arg87His (c.260G>A)?

AlphaMissense predicts likely benign (score 0.1766) — an in-silico prediction, not a clinical call.

ERCC4 p.Arg87His

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

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

c.260G>A · rs371487368 · VCV541246

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1766 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum group F

Computational evidence

Protein change
AlphaMissense	0.1766	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.015% Admixed American · 9/59,984 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00477% 77/1,613,594 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.105%	955
Admixed Americangrpmax	0.015%	6,665
Remaining individualsnot grpmax-eligible	0.00961%	10,410
East Asian	0.00446%	22,435
South Asian	0.00329%	30,352
European (non-Finnish)	0.0022%	45,375

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg87His
Coding: c.260G>A
MANE Select: NM_005236
dbSNP: rs371487368
Type: single nucleotide variant
Location: chr16:13922083 (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 87: 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.Arg87Cys 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-arg87his (accessed [today's date]).

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