Is CUL1 p.Lys522Arg (c.1565A>G) pathogenic?

CUL1 p.Lys522Arg (c.1565A>G) is classified Uncertain significance in CUL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.0662); Ultra-rare (popmax 0.04%, amr).

How common is CUL1 p.Lys522Arg (c.1565A>G) in the general population?

CUL1 p.Lys522Arg (c.1565A>G) is ultra-rare (popmax 0.04%, amr) (gnomAD).

What do computational predictors say about CUL1 p.Lys522Arg (c.1565A>G)?

AlphaMissense predicts likely benign (score 0.0662) — an in-silico prediction, not a clinical call.

CUL1 p.Lys522Arg

c.1565A>G · rs772840982 · VCV2392234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0662 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0662	likely benign
REVEL	0.339	indeterminate
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 9,420 bp · p 5.9e-17 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% Admixed American · 24/60,004 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00155% 25/1,613,966 alleles · ultra-rare exomes 22/1,461,742 · genomes 3/152,224 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.04%	2,500
East Asian	0.00223%	44,890

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: CUL1
Protein: p.Lys522Arg
Coding: c.1565A>G
MANE Select: NM_003592
dbSNP: rs772840982
Type: single nucleotide variant
Location: chr7:148788642 (GRCh38)
Gene constraint: LOEUF 0.294 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.23 · 48 PDB
Residue 522: an α-helix

Full CUL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CUL1 c.141-1G>A Uncertain significance ★ same type
CUL1 p.Ala266Ser Uncertain significance ★ ⚠ same type
CUL1 p.Ala656Val Uncertain significance ★ ⚠ same type
CUL1 p.Ala65Val Uncertain significance ★ ⚠ same type
CUL1 p.Arg321His Uncertain significance ★ ⚠ same type
CUL1 p.Arg5Gln Uncertain significance ★ ⚠ same type
CUL1 p.Arg5Trp Uncertain significance ★ ⚠ same type
CUL1 p.Arg63Ter Uncertain significance ★ 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/cul1-p-lys522arg (accessed [today's date]).

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