Is CUBN p.Arg3117His (c.9350G>A) pathogenic?

CUBN p.Arg3117His (c.9350G>A) is classified Uncertain significance in CUBN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-05). AlphaMissense: likely benign (0.0764); Ultra-rare (popmax 0.0267%, amr); Associated with Imerslund-Grasbeck syndrome type 1.

What condition is associated with CUBN p.Arg3117His (c.9350G>A)?

CUBN p.Arg3117His (c.9350G>A) is associated with Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome, proteinuria, chronic benign (ClinVar).

How common is CUBN p.Arg3117His (c.9350G>A) in the general population?

CUBN p.Arg3117His (c.9350G>A) is ultra-rare (popmax 0.0267%, amr) (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.Arg3117His (c.9350G>A)?

AlphaMissense predicts likely benign (score 0.0764) — an in-silico prediction, not a clinical call.

CUBN p.Arg3117His

c.9350G>A · rs184750323 · VCV2159615

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0764 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Imerslund-Grasbeck syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0764	likely benign
REVEL	0.043	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 2	GERP -3, phastCons 0.001
Regional constraint	o/e 1.00	unconstrained · MANE · 79 kb · p 0.98 · regional, not allelic
Overall
CADD	13.97	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 0.0267% Admixed American · 16/60,016 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00217% 35/1,614,024 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,751
Finnishnot grpmax-eligible	0.00938%	10,666
South Asian	0.00439%	22,769
Remaining individualsnot grpmax-eligible	0.0032%	31,255
East Asian	0.00223%	44,876
African / African-American	0.00133%	75,016
European (non-Finnish)	0.000424%	235,990

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.Arg3117His
Coding: c.9350G>A
MANE Select: NM_001081
dbSNP: rs184750323
Type: single nucleotide variant
Location: chr10:16869740 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3117: a UniProt-annotated variant site (in prochob); the cub 23 domain

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 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-arg3117his (accessed [today's date]).

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