Is CUBN p.Val1591Ile (c.4771G>A) pathogenic?

CUBN p.Val1591Ile (c.4771G>A) is classified Uncertain significance in CUBN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-15). AlphaMissense: likely benign (0.0626); Ultra-rare (popmax 0.01%, amr); Associated with Imerslund-Grasbeck syndrome type 1.

What condition is associated with CUBN p.Val1591Ile (c.4771G>A)?

CUBN p.Val1591Ile (c.4771G>A) is associated with Imerslund-Grasbeck syndrome type 1, proteinuria, chronic benign (ClinVar).

How common is CUBN p.Val1591Ile (c.4771G>A) in the general population?

CUBN p.Val1591Ile (c.4771G>A) is ultra-rare (popmax 0.01%, amr) (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.Val1591Ile (c.4771G>A)?

AlphaMissense predicts likely benign (score 0.0626) — an in-silico prediction, not a clinical call.

CUBN p.Val1591Ile

c.4771G>A · VCV3593188

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0626 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Imerslund-Grasbeck syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0626	likely benign
REVEL	0.055	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 0.54	GERP -2.9, phastCons 0.26
Regional constraint	o/e 1.05	unconstrained · MANE · 84 kb · p 0.074 · regional, not allelic
Overall
CADD	12.02	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 0.01% Admixed American · 6/59,982 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000743% 12/1,614,020 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,997
South Asian	0.0011%	91,074
European (non-Finnish)	0.000424%	236,003

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.Val1591Ile
Coding: c.4771G>A
MANE Select: NM_001081
Type: single nucleotide variant
Location: chr10:16954473 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1591: a UniProt-annotated variant site (in prochob); the cub 10 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: proteinuria, chronic benign

For Imerslund-Gräsbeck syndrome (Orphanet):

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

Similar variants

CUBN p.Val1591Leu Uncertain significance ★★ ⚠ same residue
CUBN p.Val1591= Likely benign ★ same residue
CUBN c.1230+1G>A Pathogenic/Likely pathogenic ★★ same condition
CUBN c.3672+2T>C 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-val1591ile (accessed [today's date]).

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