Is ERCC4 p.Asp762Glu (c.2286C>G) pathogenic?

ERCC4 p.Asp762Glu (c.2286C>G) is classified Uncertain significance in ERCC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-01). AlphaMissense: ambiguous (0.3768); Very rare (popmax 8.47e-05%, nfe).

How common is ERCC4 p.Asp762Glu (c.2286C>G) in the general population?

ERCC4 p.Asp762Glu (c.2286C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ERCC4 p.Asp762Glu (c.2286C>G)?

AlphaMissense predicts ambiguous (score 0.3768) — an in-silico prediction, not a clinical call.

ERCC4 p.Asp762Glu

c.2286C>G · rs1403769639 · VCV1336160

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3768	ambiguous
REVEL	0.307	indeterminate
SaProt	LLR -9.20	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.098	GERP -0.18, phastCons 0.92
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	22.6	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 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.84e-05% 1/1,461,888 alleles · very rare

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.Asp762Glu
Coding: c.2286C>G
MANE Select: NM_005236
dbSNP: rs1403769639
Type: single nucleotide variant
Location: chr16:13947882 (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 762: the ercc4 domain; the 'nuclease' region

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

Similar variants

ERCC4 c.1102+1G>T Likely pathogenic ★★ same type
ERCC4 c.793-2A>G Pathogenic ★★ same type
ERCC4 p.Arg20Ter Pathogenic ★★ same type
ERCC4 p.Arg589Trp Pathogenic/Likely pathogenic ★★ same type
ERCC4 p.Arg689Ser Likely pathogenic ★★ same type
ERCC4 p.Arg772Ter Pathogenic/Likely pathogenic ★★ same type
ERCC4 p.Cys236Arg Pathogenic/Likely pathogenic ★★ same type
ERCC4 p.Cys723Ter Pathogenic/Likely pathogenic ★★ same type

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-asp762glu (accessed [today's date]).

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