Is CUBN p.Ser1459Cys (c.4376C>G) pathogenic?

CUBN p.Ser1459Cys (c.4376C>G) is classified Uncertain significance in CUBN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-15). AlphaMissense: ambiguous (0.4353); Rare (popmax 0.119%, afr); Associated with Imerslund-Grasbeck syndrome type 1.

What condition is associated with CUBN p.Ser1459Cys (c.4376C>G)?

CUBN p.Ser1459Cys (c.4376C>G) is associated with Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome, proteinuria, chronic benign (ClinVar).

How common is CUBN p.Ser1459Cys (c.4376C>G) in the general population?

CUBN p.Ser1459Cys (c.4376C>G) is rare (popmax 0.119%, 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.Ser1459Cys (c.4376C>G)?

AlphaMissense predicts ambiguous (score 0.4353) — an in-silico prediction, not a clinical call.

CUBN p.Ser1459Cys

c.4376C>G · rs138022214 · VCV373457

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4353 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.119%, afr)

Conditions

Imerslund-Grasbeck syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.4353	ambiguous
REVEL	0.433	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 84 kb · p 0.074 · regional, not allelic
Overall
CADD	27.4	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 0.119% African / African-American · 89/75,038 alleles

Filtering AF 0.0987% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0913%

Overall 0.00675% 109/1,614,146 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.119%	843
Remaining individualsnot grpmax-eligible	0.0144%	6,945
Admixed American	0.00833%	12,001
South Asian	0.0011%	91,086
European (non-Finnish)	0.000424%	236,003

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.Ser1459Cys
Coding: c.4376C>G
MANE Select: NM_001081
dbSNP: rs138022214
Type: single nucleotide variant
Location: chr10:16984254 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1459: a disulfide bond; the cub 9 domain; a UniProt-annotated variant site (in prochob)

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 proteinuria, chronic benign

For Imerslund-Gräsbeck syndrome (Orphanet):

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

Similar variants

CUBN p.Ser1459Ala Uncertain significance ★ ⚠ same residue
CUBN p.Ser1459Phe 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-ser1459cys (accessed [today's date]).

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