Is CUBN p.Phe728Leu (c.2182T>C) pathogenic?

CUBN p.Phe728Leu (c.2182T>C) is classified Benign/Likely benign in CUBN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-18). AlphaMissense: ambiguous (0.5217); Rare (popmax 0.653%, afr); Associated with Imerslund-Grasbeck syndrome type 1.

What condition is associated with CUBN p.Phe728Leu (c.2182T>C)?

CUBN p.Phe728Leu (c.2182T>C) is associated with Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome (ClinVar).

How common is CUBN p.Phe728Leu (c.2182T>C) in the general population?

CUBN p.Phe728Leu (c.2182T>C) is rare (popmax 0.653%, 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.Phe728Leu (c.2182T>C)?

AlphaMissense predicts ambiguous (score 0.5217) — an in-silico prediction, not a clinical call.

CUBN p.Phe728Leu

c.2182T>C · rs147752521 · VCV299512

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5217 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.653%, afr)

Conditions

Imerslund-Grasbeck syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.5217	ambiguous
REVEL	0.135	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 84 kb · p 0.11 · regional, not allelic
Overall
CADD	15.4	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 0.653% African / African-American · 490/75,048 alleles

Filtering AF 0.605% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.586%

Overall 0.0482% 778/1,614,088 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.653%	153
Ashkenazi Jewishnot grpmax-eligible	0.182%	548
Middle Eastern	0.0829%	1,207
Remaining individualsnot grpmax-eligible	0.072%	1,389
Admixed American	0.0533%	1,876
European (non-Finnish)	0.0128%	7,815
South Asian	0.0011%	91,074

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.Phe728Leu
Coding: c.2182T>C
MANE Select: NM_001081
dbSNP: rs147752521
Type: single nucleotide variant
Location: chr10:17084390 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 728: the cub 3 domain; a disulfide bond

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.Phe728= Likely benign ★ 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-phe728leu (accessed [today's date]).

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