Is CUBN p.Met2Val (c.4A>G) pathogenic?

CUBN p.Met2Val (c.4A>G) is classified Uncertain significance in CUBN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-16). AlphaMissense: likely benign (0.1085); Ultra-rare (popmax 0.032%, afr); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with CUBN p.Met2Val (c.4A>G)?

CUBN p.Met2Val (c.4A>G) is associated with Imerslund-Grasbeck syndrome (ClinVar).

How common is CUBN p.Met2Val (c.4A>G) in the general population?

CUBN p.Met2Val (c.4A>G) is ultra-rare (popmax 0.032%, 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.Met2Val (c.4A>G)?

AlphaMissense predicts likely benign (score 0.1085) — an in-silico prediction, not a clinical call.

CUBN p.Met2Val

c.4A>G · rs200499216 · VCV2860396

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1085 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.032%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Imerslund-Grasbeck syndrome

Computational evidence

Protein change
AlphaMissense	0.1085	likely benign
REVEL	0.248	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 0.071	GERP -3.1
Regional constraint	o/e 1.04	unconstrained · MANE · 84 kb · p 0.11 · regional, not allelic
Overall
CADD	5.487	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.032% African / African-American · 24/75,044 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.00155% 25/1,614,074 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.032%	3,127
Remaining individualsnot grpmax-eligible	0.0016%	62,494

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.Met2Val
Coding: c.4A>G
MANE Select: NM_001081
dbSNP: rs200499216
Type: single nucleotide variant
Location: chr10:17129762 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

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

Disease context

Imerslund-Grasbeck syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Imerslund-Gräsbeck syndrome (Orphanet):

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

Similar variants

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
CUBN p.Arg1487Ter 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-met2val (accessed [today's date]).

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