Is ERCC6 p.Arg850Lys (c.2549G>A) pathogenic?

ERCC6 p.Arg850Lys (c.2549G>A) is classified Benign in ERCC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-27). AlphaMissense: likely benign (0.0891); Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ERCC6 p.Arg850Lys (c.2549G>A)?

AlphaMissense predicts likely benign (score 0.0891) — an in-silico prediction, not a clinical call.

ERCC6 p.Arg850Lys

Q: How common is ERCC6 p.Arg850Lys (c.2549G>A) in the general population?

ERCC6 p.Arg850Lys (c.2549G>A) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2549G>A · rs4253072 · VCV1266989

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0891 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0891	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -4.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -1.9
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	11.54	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 R382K vs ClinVar R850K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 100% East Asian · 44,886/44,886 alleles

Filtering AF 99.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.8%

Overall 99.9% 1,612,378/1,614,208 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	100%	1
Finnishnot grpmax-eligible	100%	1
Ashkenazi Jewishnot grpmax-eligible	100%	1
Amishnot grpmax-eligible	100%	1
South Asian	100%	1
European (non-Finnish)	100%	1
Remaining individualsnot grpmax-eligible	99.8%	1
Admixed American	99.8%	1
Middle Eastern	99.7%	1
African / African-American	98.3%	1

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.Arg850Lys
Coding: c.2549G>A
MANE Select: NM_000124 · reported on NM_001277058
dbSNP: rs4253072
Type: single nucleotide variant
Location: chr10:49515970 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 850: a UniProt-annotated variant site (in); an α-helix; the helicase c-terminal domain

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

Similar variants

ERCC6 p.Ile850Val Uncertain significance ★ ⚠ same residue
ERCC6 p.Ile850fs Likely pathogenic ★ 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
ERCC6 c.2287-2A>G 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-arg850lys (accessed [today's date]).

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