Is CUBN p.Val1989= (c.5967G>C) pathogenic?

CUBN p.Val1989= (c.5967G>C) is classified Conflicting classifications of pathogenicity in CUBN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-01). Rare (popmax 0.411%, afr); Associated with Imerslund-Grasbeck syndrome type 1.

What condition is associated with CUBN p.Val1989= (c.5967G>C)?

CUBN p.Val1989= (c.5967G>C) is associated with Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome (ClinVar).

How common is CUBN p.Val1989= (c.5967G>C) in the general population?

CUBN p.Val1989= (c.5967G>C) is rare (popmax 0.411%, afr) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CUBN p.Val1989=

c.5967G>C · rs139153235 · VCV299447

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.411%, afr)

Conditions

Imerslund-Grasbeck syndrome type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.54	GERP -2.8, phastCons 0.039
Overall
CADD	0.338	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.411% African / African-American · 308/75,012 alleles

Filtering AF 0.373% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.358%

Overall 0.0202% 326/1,613,966 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.411%	244
Middle Eastern	0.0332%	3,008
Admixed American	0.0167%	6,001
Remaining individualsnot grpmax-eligible	0.0048%	20,830
South Asian	0.0011%	91,074
European (non-Finnish)	0.000169%	589,998

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.Val1989=
Coding: c.5967G>C
MANE Select: NM_001081
dbSNP: rs139153235
Type: single nucleotide variant
Location: chr10:16933244 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1989: a disulfide bond; a UniProt-annotated variant site (in prochob); the cub 14 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

For Imerslund-Gräsbeck syndrome (Orphanet):

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

Similar variants

CUBN p.Val1989Met 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
CUBN c.6822-1G>A 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-val1989 (accessed [today's date]).

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