Is CUBN p.Asp2455Glu (c.7365T>A) pathogenic?

CUBN p.Asp2455Glu (c.7365T>A) is classified Benign/Likely benign in CUBN (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1334); Rare (popmax 0.796%, nfe); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with CUBN p.Asp2455Glu (c.7365T>A)?

CUBN p.Asp2455Glu (c.7365T>A) is associated with Imerslund-Grasbeck syndrome, Imerslund-Grasbeck syndrome type 1 (ClinVar).

How common is CUBN p.Asp2455Glu (c.7365T>A) in the general population?

CUBN p.Asp2455Glu (c.7365T>A) is rare (popmax 0.796%, 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.Asp2455Glu (c.7365T>A)?

AlphaMissense predicts likely benign (score 0.1334) — an in-silico prediction, not a clinical call.

CUBN p.Asp2455Glu

c.7365T>A · rs117128556 · VCV299424

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1334 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.796%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Imerslund-Grasbeck syndrome

Computational evidence

Protein change
AlphaMissense	0.1334	likely benign
REVEL	0.027	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 0.17	GERP -0.72, phastCons 0.023
Regional constraint	o/e 1.05	unconstrained · MANE · 84 kb · p 0.074 · regional, not allelic
Overall
CADD	5.472	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 0.796% European (non-Finnish) · 9,398/1,180,008 alleles

Filtering AF 0.783% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.777%

Overall 0.67% 10,816/1,614,016 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.796%	126
Middle Eastern	0.775%	129
Finnishnot grpmax-eligible	0.719%	139
Remaining individualsnot grpmax-eligible	0.63%	159
Admixed American	0.472%	212
South Asian	0.134%	746
African / African-American	0.132%	758
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,277

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.Asp2455Glu
Coding: c.7365T>A
MANE Select: NM_001081
dbSNP: rs117128556
Type: single nucleotide variant
Location: chr10:16913979 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2455: a disulfide bond; a UniProt-annotated variant site (in prochob); the cub 18 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: 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 p.Asp2455Tyr Uncertain significance ★★ ⚠ same residue
CUBN p.Asp2455Ala 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-asp2455glu (accessed [today's date]).

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