Is ERCC6 p.Arg683Gln (c.2048G>A) pathogenic?

ERCC6 p.Arg683Gln (c.2048G>A) is classified Conflicting classifications of pathogenicity in ERCC6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.1163); Ultra-rare (popmax 0.0267%, amr); Associated with cerebrooculofacioskeletal syndrome 1.

What condition is associated with ERCC6 p.Arg683Gln (c.2048G>A)?

ERCC6 p.Arg683Gln (c.2048G>A) is associated with cerebrooculofacioskeletal syndrome 1, lung cancer, de Sanctis-Cacchione syndrome (ClinVar).

How common is ERCC6 p.Arg683Gln (c.2048G>A) in the general population?

ERCC6 p.Arg683Gln (c.2048G>A) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about ERCC6 p.Arg683Gln (c.2048G>A)?

AlphaMissense predicts likely benign (score 0.1163) — an in-silico prediction, not a clinical call.

ERCC6 p.Arg683Gln

c.2048G>A · rs148845653 · VCV193557

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1163 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cerebrooculofacioskeletal syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1163	likely benign
REVEL	0.34	indeterminate
SaProt	LLR -5.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.95, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	25.6	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 0.0267% Admixed American · 16/59,990 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.0172% 277/1,613,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.598%	167
Remaining individualsnot grpmax-eligible	0.0496%	2,016
Admixed Americangrpmax	0.0267%	3,749
European (non-Finnish)	0.00432%	23,136
African / African-American	0.00267%	37,465

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg683Gln
Coding: c.2048G>A
MANE Select: NM_000124
dbSNP: rs148845653
Type: single nucleotide variant
Location: chr10:49482808 (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

cerebrooculofacioskeletal syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lung cancer de Sanctis-Cacchione syndrome UV-sensitive syndrome 1 age related macular degeneration 5 premature ovarian failure 11 Cockayne syndrome type 2

Similar variants

ERCC6 p.Arg683Ter Pathogenic/Likely pathogenic ★★ 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-arg683gln (accessed [today's date]).

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