Is CUBN p.Val753Met (c.2257G>A) pathogenic?

CUBN p.Val753Met (c.2257G>A) is classified Benign/Likely benign in CUBN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-13). AlphaMissense: likely benign (0.1111); Rare (popmax 0.43%, eas); Associated with Inborn genetic diseases.

What condition is associated with CUBN p.Val753Met (c.2257G>A)?

CUBN p.Val753Met (c.2257G>A) is associated with Inborn genetic diseases, Imerslund-Grasbeck syndrome (ClinVar).

How common is CUBN p.Val753Met (c.2257G>A) in the general population?

CUBN p.Val753Met (c.2257G>A) is rare (popmax 0.43%, eas) (gnomAD).

What do computational predictors say about CUBN p.Val753Met (c.2257G>A)?

AlphaMissense predicts likely benign (score 0.1111) — an in-silico prediction, not a clinical call.

CUBN p.Val753Met

c.2257G>A · rs77886913 · VCV1942420

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1111 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.43%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1111	likely benign
REVEL	0.063	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 0.27	GERP -1, phastCons 0.019
Regional constraint	o/e 1.04	unconstrained · MANE · 84 kb · p 0.11 · regional, not allelic
Overall
CADD	12.63	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 0.43% East Asian · 193/44,884 alleles

Filtering AF 0.38% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.361%

Overall 0.0136% 220/1,614,108 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.43%	233
Remaining individualsnot grpmax-eligible	0.0176%	5,682
South Asian	0.0022%	45,537
European (non-Finnish)	0.00119%	84,287

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.Val753Met
Coding: c.2257G>A
MANE Select: NM_001081
dbSNP: rs77886913
Type: single nucleotide variant
Location: chr10:17084315 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 753: 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

Similar variants

CUBN p.Val753Glu 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.3829+1G>A Pathogenic/Likely pathogenic ★★ same condition
CUBN c.4350+2T>C Likely pathogenic ★★ same condition
CUBN c.6822-1G>A Likely pathogenic ★★ same condition
CUBN c.8598+1G>T Likely pathogenic ★★ same condition
CUBN c.9454+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-val753met (accessed [today's date]).

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