Is ERCC6L2 p.Val593Asp (c.1778T>A) pathogenic?

ERCC6L2 p.Val593Asp (c.1778T>A) is classified Uncertain significance in ERCC6L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-03). Very rare (popmax 0.000509%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ERCC6L2 p.Val593Asp (c.1778T>A)?

ERCC6L2 p.Val593Asp (c.1778T>A) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC6L2 p.Val593Asp (c.1778T>A) in the general population?

ERCC6L2 p.Val593Asp (c.1778T>A) is very rare (popmax 0.000509%, nfe) (gnomAD).

ERCC6L2 p.Val593Asp

c.1778T>A · VCV4618777

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.712	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.37, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 92 kb · p 1.5e-06 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000509% European (non-Finnish) · 6/1,179,572 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,210 alleles · very rare exomes 6/1,461,070 · genomes 0/152,140 · 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.Val593Asp
Coding: c.1778T>A
MANE Select: NM_020207
Type: single nucleotide variant
Location: chr9:95941480 (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 593: the helicase c-terminal 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.Val593= Likely benign ★★ same residue
ERCC6L2 p.Val593Ala Uncertain significance ★ same residue
ERCC6L2 p.Val593Leu Uncertain significance ★ same residue
ERCC6L2 p.Val593Phe Uncertain significance ★ same residue
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

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-val593asp (accessed [today's date]).

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