Is ERCC6L2 p.Pro280= (c.840A>G) pathogenic?

ERCC6L2 p.Pro280= (c.840A>G) is classified Likely benign in ERCC6L2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-25). Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ERCC6L2 p.Pro280= (c.840A>G)?

ERCC6L2 p.Pro280= (c.840A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC6L2 p.Pro280= (c.840A>G) in the general population?

ERCC6L2 p.Pro280= (c.840A>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

ERCC6L2 p.Pro280=

c.840A>G · rs779755641 · VCV1918804

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

Inborn genetic diseases

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 -0.068	GERP -0.74, phastCons 0.01
Overall
CADD	9.912	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,890 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,872 alleles · very rare exomes 2/1,461,626 · genomes 1/152,246 · joint denominator

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: ERCC6L2
Protein: p.Pro280=
Coding: c.840A>G
MANE Select: NM_020207
dbSNP: rs779755641
Type: single nucleotide variant
Location: chr9:95915719 (GRCh38)
Gene constraint: LOEUF 0.792 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 58.11 · 2 PDB
Residue 280: the helicase atp-binding domain

Full ERCC6L2 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

Similar variants

ERCC6L2 p.Ala26Val Uncertain significance ★★ same condition
ERCC6L2 p.Ala290Val Uncertain significance ★★ same condition
ERCC6L2 p.Ala345Thr Uncertain significance ★★ same condition
ERCC6L2 p.Ala37Thr Uncertain significance ★★ same condition
ERCC6L2 p.Ala460Thr Uncertain significance ★★ same condition
ERCC6L2 p.Ala464Val Uncertain significance ★★ same condition
ERCC6L2 p.Ala465Gly Uncertain significance ★★ same condition
ERCC6L2 p.Ala546Ser 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/ercc6l2-p-pro280 (accessed [today's date]).

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