Is CUBN p.Tyr3099= (c.9297C>T) pathogenic?

CUBN p.Tyr3099= (c.9297C>T) is classified Likely benign in CUBN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-21). Very rare (popmax 0.00223%, eas); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with CUBN p.Tyr3099= (c.9297C>T)?

CUBN p.Tyr3099= (c.9297C>T) is associated with Imerslund-Grasbeck syndrome, proteinuria, chronic benign, Imerslund-Grasbeck syndrome type 1 (ClinVar).

How common is CUBN p.Tyr3099= (c.9297C>T) in the general population?

CUBN p.Tyr3099= (c.9297C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

CUBN p.Tyr3099=

c.9297C>T · rs754292924 · VCV1127819

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Imerslund-Grasbeck syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3	GERP -3
Overall
CADD	0.135	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,884 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00136% 22/1,613,940 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,828
East Asiangrpmax	0.00223%	44,884
Admixed American	0.00167%	60,008
European (non-Finnish)	0.00144%	69,408

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Tyr3099=
Coding: c.9297C>T
MANE Select: NM_001081
dbSNP: rs754292924
Type: single nucleotide variant
Location: chr10:16869793 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3099: a disulfide bond; a UniProt-annotated variant site (in prochob); the cub 23 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: proteinuria, chronic benign 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-tyr3099 (accessed [today's date]).

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