Is CUBN p.Ser3293Leu (c.9878C>T) pathogenic?

CUBN p.Ser3293Leu (c.9878C>T) is classified Uncertain significance in CUBN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-21). AlphaMissense: likely benign (0.0789); Ultra-rare (popmax 0.0176%, sas); Associated with proteinuria, chronic benign.

What condition is associated with CUBN p.Ser3293Leu (c.9878C>T)?

CUBN p.Ser3293Leu (c.9878C>T) is associated with proteinuria, chronic benign, Imerslund-Grasbeck syndrome, Imerslund-Grasbeck syndrome type 1 (ClinVar).

How common is CUBN p.Ser3293Leu (c.9878C>T) in the general population?

CUBN p.Ser3293Leu (c.9878C>T) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

What do computational predictors say about CUBN p.Ser3293Leu (c.9878C>T)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

CUBN p.Ser3293Leu

c.9878C>T · rs566296480 · VCV1023962

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Conditions

proteinuria, chronic benign

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.521	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.42, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 79 kb · p 0.98 · regional, not allelic
Overall
CADD	26.3	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 0.0176% South Asian · 16/90,870 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.009%

Overall 0.00205% 33/1,613,202 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,679
Admixed American	0.0134%	7,486
Remaining individualsnot grpmax-eligible	0.0032%	31,236
East Asian	0.00223%	44,866
African / African-American	0.00133%	75,042
European (non-Finnish)	0.000424%	235,908

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.Ser3293Leu
Coding: c.9878C>T
MANE Select: NM_001081
dbSNP: rs566296480
Type: single nucleotide variant
Location: chr10:16840484 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3293: a disulfide bond; a UniProt-annotated variant site (in prochob); the cub 25 domain

Full CUBN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

proteinuria, chronic benign — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Imerslund-Grasbeck syndrome Imerslund-Grasbeck syndrome type 1

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-ser3293leu (accessed [today's date]).

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