Is ERCC6 p.Arg562Trp (c.1684A>T) pathogenic?

ERCC6 p.Arg562Trp (c.1684A>T) is classified Likely pathogenic in ERCC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-02). AlphaMissense: likely benign (0.2761); Very rare (popmax 0.00223%, eas); Associated with cerebrooculofacioskeletal syndrome 1.

What condition is associated with ERCC6 p.Arg562Trp (c.1684A>T)?

ERCC6 p.Arg562Trp (c.1684A>T) is associated with cerebrooculofacioskeletal syndrome 1 (ClinVar).

How common is ERCC6 p.Arg562Trp (c.1684A>T) in the general population?

ERCC6 p.Arg562Trp (c.1684A>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ERCC6 p.Arg562Trp (c.1684A>T)?

AlphaMissense predicts likely benign (score 0.2761) — an in-silico prediction, not a clinical call.

ERCC6 p.Arg562Trp

c.1684A>T · rs777252763 · VCV1320117

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2761 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebrooculofacioskeletal syndrome 1

Computational evidence

Protein change
AlphaMissense	0.2761	likely benign ⚠ discordant with ClinVar
REVEL	0.698	pathogenic-leaning
SaProt	LLR -9.40	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.23	donor loss, 1 bp away · masked 0 · deltas
Pangolin	Δ0.59	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	34.0	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 0.00223% East Asian · 1/44,882 alleles

Overall 6.84e-05% 1/1,461,506 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.Arg562Trp
Coding: c.1684A>T
MANE Select: NM_000124
dbSNP: rs777252763
Type: single nucleotide variant
Location: chr10:49500539 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 562: the 'disordered' region; the helicase atp-binding domain

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

Similar variants

ERCC6 p.Arg562Ser 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
ERCC6 c.2599-26A>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-arg562trp (accessed [today's date]).

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