Is CUBN p.Ala2252Val (c.6755C>T) pathogenic?

CUBN p.Ala2252Val (c.6755C>T) is classified Uncertain significance in CUBN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-29). AlphaMissense: likely benign (0.1043); Very rare (popmax 0.0022%, sas); Associated with Imerslund-Grasbeck syndrome type 1.

What condition is associated with CUBN p.Ala2252Val (c.6755C>T)?

CUBN p.Ala2252Val (c.6755C>T) is associated with Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome, proteinuria, chronic benign (ClinVar).

How common is CUBN p.Ala2252Val (c.6755C>T) in the general population?

CUBN p.Ala2252Val (c.6755C>T) is very rare (popmax 0.0022%, sas) (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.Ala2252Val (c.6755C>T)?

AlphaMissense predicts likely benign (score 0.1043) — an in-silico prediction, not a clinical call.

CUBN p.Ala2252Val

c.6755C>T · rs529856485 · VCV2159644

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1043 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Imerslund-Grasbeck syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.1043	likely benign
REVEL	0.075	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 3.6	GERP -3.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 84 kb · p 0.074 · regional, not allelic
Overall
CADD	17.09	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 0.0022% South Asian · 2/91,060 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.00031% 5/1,613,726 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,530
European (non-Finnish)	0.000254%	393,317

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.Ala2252Val
Coding: c.6755C>T
MANE Select: NM_001081
dbSNP: rs529856485
Type: single nucleotide variant
Location: chr10:16920029 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2252: a UniProt-annotated variant site (in prochob); a UniProt-annotated variant site (in a colorectal cancer sample; somatic mutation); the cub 16 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 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-ala2252val (accessed [today's date]).

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