Is ERCC4 p.Ala860Asp (c.2579C>A) pathogenic?

ERCC4 p.Ala860Asp (c.2579C>A) is classified Conflicting classifications of pathogenicity in ERCC4 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-31). AlphaMissense: ambiguous (0.3792); Rare (popmax 0.849%, afr); Associated with Inborn genetic diseases.

What condition is associated with ERCC4 p.Ala860Asp (c.2579C>A)?

ERCC4 p.Ala860Asp (c.2579C>A) is associated with Inborn genetic diseases, Hutchinson-Gilford progeria syndrome, xeroderma pigmentosum group F (ClinVar).

How common is ERCC4 p.Ala860Asp (c.2579C>A) in the general population?

ERCC4 p.Ala860Asp (c.2579C>A) is rare (popmax 0.849%, afr) (gnomAD).

What do computational predictors say about ERCC4 p.Ala860Asp (c.2579C>A)?

AlphaMissense predicts ambiguous (score 0.3792) — an in-silico prediction, not a clinical call.

ERCC4 p.Ala860Asp

c.2579C>A · rs4986933 · VCV134138

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

ambiguous

0.3792 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.849%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3792	ambiguous
REVEL	0.218	benign-leaning
SaProt	LLR -10.16	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	25.4	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 0.849% African / African-American · 637/75,010 alleles

Filtering AF 0.795% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.773%

Overall 0.0475% 767/1,614,134 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.849%	118
Middle Eastern	0.099%	1,010
Admixed American	0.09%	1,112
Remaining individualsnot grpmax-eligible	0.0672%	1,488
South Asian	0.00769%	13,011
European (non-Finnish)	0.00178%	56,192

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.Ala860Asp
Coding: c.2579C>A
MANE Select: NM_005236
dbSNP: rs4986933
Type: single nucleotide variant
Location: chr16:13948175 (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 860: a UniProt-annotated variant site (in); an α-helix; the 'hhh2, dimerization with ercc1' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Hutchinson-Gilford progeria syndrome xeroderma pigmentosum group F Fanconi anemia complementation group Q hereditary neoplastic syndrome Cockayne syndrome xeroderma pigmentosum

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-ala860asp (accessed [today's date]).

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