Is CUBN p.Val735Ile (c.2203G>A) pathogenic?

CUBN p.Val735Ile (c.2203G>A) is classified Conflicting classifications of pathogenicity in CUBN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2023-11-07). AlphaMissense: likely benign (0.0615); Ultra-rare (popmax 0.0401%, eas); Associated with Inborn genetic diseases.

What condition is associated with CUBN p.Val735Ile (c.2203G>A)?

CUBN p.Val735Ile (c.2203G>A) is associated with Inborn genetic diseases, Imerslund-Grasbeck syndrome, proteinuria, chronic benign (ClinVar).

How common is CUBN p.Val735Ile (c.2203G>A) in the general population?

CUBN p.Val735Ile (c.2203G>A) is ultra-rare (popmax 0.0401%, eas) (gnomAD).

What do computational predictors say about CUBN p.Val735Ile (c.2203G>A)?

AlphaMissense predicts likely benign (score 0.0615) — an in-silico prediction, not a clinical call.

CUBN p.Val735Ile

c.2203G>A · rs370770104 · VCV299510

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0615 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0615	likely benign
REVEL	0.09	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8	GERP -3.7
Regional constraint	o/e 1.04	unconstrained · MANE · 84 kb · p 0.11 · regional, not allelic
Overall
CADD	0.002	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 0.0401% East Asian · 18/44,892 alleles

Filtering AF 0.0258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0213%

Overall 0.0101% 163/1,614,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0401%	2,494
European (non-Finnish)	0.0116%	8,613
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00267%	37,461
South Asian	0.0022%	45,542
Admixed American	0.00167%	60,004

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.Val735Ile
Coding: c.2203G>A
MANE Select: NM_001081
dbSNP: rs370770104
Type: single nucleotide variant
Location: chr10:17084369 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 735: the cub 3 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Imerslund-Grasbeck syndrome proteinuria, chronic benign Imerslund-Grasbeck syndrome type 1

Similar variants

CUBN p.Val735= 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-val735ile (accessed [today's date]).

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