Is ERCC4 p.Leu798Val (c.2392C>G) pathogenic?

ERCC4 p.Leu798Val (c.2392C>G) is classified Uncertain significance in ERCC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-28). AlphaMissense: likely benign (0.21); Ultra-rare (popmax 0.012%, afr); Associated with xeroderma pigmentosum.

What condition is associated with ERCC4 p.Leu798Val (c.2392C>G)?

ERCC4 p.Leu798Val (c.2392C>G) is associated with xeroderma pigmentosum (ClinVar).

How common is ERCC4 p.Leu798Val (c.2392C>G) in the general population?

ERCC4 p.Leu798Val (c.2392C>G) is ultra-rare (popmax 0.012%, afr) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

What do computational predictors say about ERCC4 p.Leu798Val (c.2392C>G)?

AlphaMissense predicts likely benign (score 0.21) — an in-silico prediction, not a clinical call.

ERCC4 p.Leu798Val

c.2392C>G · rs369736388 · VCV1692884

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.21 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
AlphaMissense	0.21	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -12.36	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.95, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	23.3	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 0.012% African / African-American · 9/75,044 alleles

Filtering AF 0.00622% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000558% 9/1,614,190 alleles · ultra-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.Leu798Val
Coding: c.2392C>G
MANE Select: NM_005236
dbSNP: rs369736388
Type: single nucleotide variant
Location: chr16:13947988 (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 798: the 'nuclease' region

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

Disease context

xeroderma pigmentosum — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Xeroderma pigmentosum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

ERCC4 p.Leu798= Likely benign ★ same residue
ERCC4 c.1102+1G>T Likely pathogenic ★★ same condition
ERCC4 p.Arg589Trp Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Asn893Asp Uncertain significance ★★ ⚠ same condition
ERCC4 p.Gln406Arg Uncertain significance ★★ ⚠ same condition
ERCC4 p.Glu368Lys Uncertain significance ★★ ⚠ same condition
ERCC4 p.Glu527Asp Uncertain significance ★★ ⚠ same condition
ERCC4 p.Gly403Arg Uncertain significance ★★ ⚠ 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-leu798val (accessed [today's date]).

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