Is ERCC6 p.Asp507Val (c.1520A>T) pathogenic?

ERCC6 p.Asp507Val (c.1520A>T) is classified Uncertain significance in ERCC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-01). AlphaMissense: likely pathogenic (0.7733); Very rare (popmax 8.48e-05%, nfe).

How common is ERCC6 p.Asp507Val (c.1520A>T) in the general population?

ERCC6 p.Asp507Val (c.1520A>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ERCC6 p.Asp507Val (c.1520A>T)?

AlphaMissense predicts likely pathogenic (score 0.7733) — an in-silico prediction, not a clinical call.

ERCC6 p.Asp507Val

c.1520A>T · rs2496104249 · VCV2640458

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7733 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7733	likely pathogenic
REVEL	0.143	moderately benign-leaning
SaProt	LLR -8.98	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.58	GERP -0.51, phastCons 0.66
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	15.88	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM D39V vs ClinVar D507V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,880 alleles

Overall 6.84e-05% 1/1,461,694 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: ERCC6
Protein: p.Asp507Val
Coding: c.1520A>T
MANE Select: NM_000124 · reported on NM_001277058
dbSNP: rs2496104249
Type: single nucleotide variant
Location: chr10:49516999 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 507: the 'disordered' region; the 'n-terminal domain; essential for its chromatin remodeling activity' region

Full ERCC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERCC6 c.1397+1G>C Likely pathogenic ★★ same type
ERCC6 c.1526+1G>T Pathogenic/Likely pathogenic ★★ same type
ERCC6 c.2169+1G>A Likely pathogenic ★★ same type
ERCC6 c.2170-1G>A Pathogenic/Likely pathogenic ★★ same type
ERCC6 c.2286+1G>A Pathogenic/Likely pathogenic ★★ same type
ERCC6 c.2287-2A>G Pathogenic/Likely pathogenic ★★ same type
ERCC6 c.2599-26A>G Pathogenic/Likely pathogenic ★★ same type
ERCC6 c.2709+1G>T 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/ercc6-p-asp507val (accessed [today's date]).

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