Is CUBN p.Lys89Gln (c.265A>C) pathogenic?

CUBN p.Lys89Gln (c.265A>C) is classified Uncertain significance in CUBN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-13). AlphaMissense: likely benign (0.1512); Very rare (popmax 0.00268%, afr); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with CUBN p.Lys89Gln (c.265A>C)?

CUBN p.Lys89Gln (c.265A>C) is associated with Imerslund-Grasbeck syndrome, Imerslund-Grasbeck syndrome type 1 (ClinVar).

How common is CUBN p.Lys89Gln (c.265A>C) in the general population?

CUBN p.Lys89Gln (c.265A>C) is very rare (popmax 0.00268%, afr) (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.Lys89Gln (c.265A>C)?

AlphaMissense predicts likely benign (score 0.1512) — an in-silico prediction, not a clinical call.

CUBN p.Lys89Gln

c.265A>C · rs755860454 · VCV1029049

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1512 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Conditions

Imerslund-Grasbeck syndrome

Computational evidence

Protein change
AlphaMissense	0.1512	likely benign
REVEL	0.452	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 84 kb · p 0.11 · regional, not allelic
Overall
CADD	24.2	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 0.00268% African / African-American · 2/74,690 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000187% 3/1,602,520 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,345
Remaining individualsnot grpmax-eligible	0.00161%	62,120

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.Lys89Gln
Coding: c.265A>C
MANE Select: NM_001081
dbSNP: rs755860454
Type: single nucleotide variant
Location: chr10:17127912 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 89: an α-helix

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 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-lys89gln (accessed [today's date]).

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