Is CUBN p.Arg520Trp (c.1558C>T) pathogenic?

CUBN p.Arg520Trp (c.1558C>T) is classified Conflicting classifications of pathogenicity in CUBN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-09-20). AlphaMissense: likely benign (0.0945); Ultra-rare (popmax 0.033%, mid); Associated with Imerslund-Grasbeck syndrome type 1.

What condition is associated with CUBN p.Arg520Trp (c.1558C>T)?

CUBN p.Arg520Trp (c.1558C>T) is associated with Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome, proteinuria, chronic benign (ClinVar).

How common is CUBN p.Arg520Trp (c.1558C>T) in the general population?

CUBN p.Arg520Trp (c.1558C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CUBN p.Arg520Trp (c.1558C>T)?

AlphaMissense predicts likely benign (score 0.0945) — an in-silico prediction, not a clinical call.

CUBN p.Arg520Trp

c.1558C>T · rs564637804 · VCV532198

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0945 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Imerslund-Grasbeck syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0945	likely benign
REVEL	0.192	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	Δ0.28	acceptor gain · deltas
Pangolin	Δ0.20	gain · loss 0.12 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.9	GERP 0.91, phastCons 0.99
Regional constraint	o/e 1.04	unconstrained · MANE · 84 kb · p 0.11 · regional, not allelic
Overall
CADD	26.3	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.00428% 69/1,613,168 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
African / African-American	0.012%	8,330
Admixed American	0.0117%	8,572
South Asian	0.00659%	15,173
East Asian	0.00446%	22,430
European (non-Finnish)	0.00339%	29,482
Remaining individualsnot grpmax-eligible	0.0032%	31,241
Finnishnot grpmax-eligible	0.00156%	63,948

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: CUBN
Protein: p.Arg520Trp
Coding: c.1558C>T
MANE Select: NM_001081
dbSNP: rs564637804
Type: single nucleotide variant
Location: chr10:17100212 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 520: the cub 1 domain

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

Disease context

Imerslund-Grasbeck syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Imerslund-Grasbeck syndrome proteinuria, chronic benign

For Imerslund-Gräsbeck syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Finland)

Similar variants

CUBN p.Arg520Gln Uncertain significance ★★ ⚠ same residue
CUBN p.Arg520Leu Uncertain significance ★ ⚠ same residue
CUBN c.10033-1G>A Likely pathogenic ★★ same condition
CUBN c.1230+1G>A Pathogenic/Likely pathogenic ★★ same condition
CUBN c.3672+2T>C Likely pathogenic ★★ same condition
CUBN c.3829+1G>A Pathogenic/Likely pathogenic ★★ same condition
CUBN c.4350+2T>C Likely pathogenic ★★ same condition
CUBN c.6821+3A>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/cubn-p-arg520trp (accessed [today's date]).

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