Is ERCC6 p.Arg557Cys (c.1669C>T) pathogenic?

ERCC6 p.Arg557Cys (c.1669C>T) is classified Uncertain significance in ERCC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-08). AlphaMissense: likely benign (0.2498); Ultra-rare (popmax 0.0267%, afr).

How common is ERCC6 p.Arg557Cys (c.1669C>T) in the general population?

ERCC6 p.Arg557Cys (c.1669C>T) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

What do computational predictors say about ERCC6 p.Arg557Cys (c.1669C>T)?

AlphaMissense predicts likely benign (score 0.2498) — an in-silico prediction, not a clinical call.

ERCC6 p.Arg557Cys

c.1669C>T · rs115582915 · VCV1703083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2498 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2498	likely benign
REVEL	0.743	pathogenic-leaning
SaProt	LLR -7.74	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	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 0.0267% African / African-American · 20/75,000 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00155% 25/1,613,854 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0267%	3,750
Admixed American	0.00167%	60,004
European (non-Finnish)	0.000339%	294,964

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.Arg557Cys
Coding: c.1669C>T
MANE Select: NM_000124
dbSNP: rs115582915
Type: single nucleotide variant
Location: chr10:49500554 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 557: the 'disordered' region; the helicase atp-binding domain

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

Similar variants

ERCC6 p.Arg557Gly Uncertain significance ★★ ⚠ same residue
ERCC6 p.Arg557His Uncertain significance ★★ ⚠ same residue
ERCC6 p.Arg557= Likely benign ★ same residue
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

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-arg557cys (accessed [today's date]).

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