Is ERCC6 p.Arg683Ter (c.2047C>T) pathogenic?

ERCC6 p.Arg683Ter (c.2047C>T) is classified Pathogenic/Likely pathogenic in ERCC6 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-09-10). Very rare (popmax 0.00542%, nfe); Associated with age related macular degeneration 5.

What condition is associated with ERCC6 p.Arg683Ter (c.2047C>T)?

ERCC6 p.Arg683Ter (c.2047C>T) is associated with age related macular degeneration 5, lung cancer, cerebrooculofacioskeletal syndrome 1 (ClinVar).

How common is ERCC6 p.Arg683Ter (c.2047C>T) in the general population?

ERCC6 p.Arg683Ter (c.2047C>T) is very rare (popmax 0.00542%, nfe) (gnomAD).

ERCC6 p.Arg683Ter

c.2047C>T · rs121917904 · VCV1711

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00542%, nfe)

Conditions

age related macular degeneration 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 21
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.9, phastCons 1
Overall
CADD	46.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00542% European (non-Finnish) · 64/1,180,006 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00396%

Overall 0.00421% 68/1,613,940 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00542%	18,438
African / African-American	0.00267%	37,444
East Asian	0.00223%	44,888
Finnishnot grpmax-eligible	0.00156%	64,016

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.Arg683Ter
Coding: c.2047C>T
MANE Select: NM_000124
dbSNP: rs121917904
Type: single nucleotide variant
Location: chr10:49482809 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 683: the helicase atp-binding domain; an α-helix

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

Disease context

Also linked: lung cancer cerebrooculofacioskeletal syndrome 1 de Sanctis-Cacchione syndrome UV-sensitive syndrome 1 premature ovarian failure 11 Cockayne syndrome type 2

Similar variants

ERCC6 p.Arg683Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ERCC6 p.Arg683Gly Uncertain significance ★ ⚠ same residue
ERCC6 c.1397+1G>C Likely pathogenic ★★ same condition
ERCC6 c.1526+1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC6 c.2169+1G>A Likely pathogenic ★★ same condition
ERCC6 c.2170-1G>A Pathogenic/Likely pathogenic ★★ same condition
ERCC6 c.2286+1G>A Pathogenic/Likely pathogenic ★★ same condition
ERCC6 c.2287-2A>G Pathogenic/Likely pathogenic ★★ 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/ercc6-p-arg683ter (accessed [today's date]).

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