Is CUBN p.Ile3047Val (c.9139A>G) pathogenic?

CUBN p.Ile3047Val (c.9139A>G) is classified Conflicting classifications of pathogenicity in CUBN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.0716); Ultra-rare (popmax 0.0123%, nfe); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with CUBN p.Ile3047Val (c.9139A>G)?

CUBN p.Ile3047Val (c.9139A>G) is associated with Imerslund-Grasbeck syndrome, proteinuria, chronic benign, Imerslund-Grasbeck syndrome type 1 (ClinVar).

How common is CUBN p.Ile3047Val (c.9139A>G) in the general population?

CUBN p.Ile3047Val (c.9139A>G) is ultra-rare (popmax 0.0123%, nfe) (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.Ile3047Val (c.9139A>G)?

AlphaMissense predicts likely benign (score 0.0716) — an in-silico prediction, not a clinical call.

CUBN p.Ile3047Val

c.9139A>G · rs376118603 · VCV850065

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0716 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Imerslund-Grasbeck syndrome

Computational evidence

Protein change
AlphaMissense	0.0716	likely benign
REVEL	0.026	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.9	GERP -3.1
Regional constraint	o/e 1.00	unconstrained · MANE · 79 kb · p 0.98 · regional, not allelic
Overall
CADD	0.112	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 0.0123% European (non-Finnish) · 145/1,180,006 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00997%

Overall 0.00942% 152/1,614,008 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0123%	8,138
Admixed American	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0048%	20,829

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.Ile3047Val
Coding: c.9139A>G
MANE Select: NM_001081
dbSNP: rs376118603
Type: single nucleotide variant
Location: chr10:16874471 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3047: a disulfide bond; a UniProt-annotated variant site (in prochob); the cub 23 domain

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

Disease context

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

Also linked: proteinuria, chronic benign Imerslund-Grasbeck syndrome type 1

For Imerslund-Gräsbeck syndrome (Orphanet):

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

Similar variants

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
CUBN c.6822-1G>A Likely pathogenic ★★ same condition
CUBN c.8598+1G>T 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-ile3047val (accessed [today's date]).

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