Is CUBN p.Arg3618Gln (c.10853G>A) pathogenic?

CUBN p.Arg3618Gln (c.10853G>A) is classified Uncertain significance in CUBN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-08). AlphaMissense: likely benign (0.0662); Ultra-rare (popmax 0.0334%, amr); Associated with proteinuria, chronic benign.

What condition is associated with CUBN p.Arg3618Gln (c.10853G>A)?

CUBN p.Arg3618Gln (c.10853G>A) is associated with proteinuria, chronic benign, Imerslund-Grasbeck syndrome, Imerslund-Grasbeck syndrome type 1 (ClinVar).

How common is CUBN p.Arg3618Gln (c.10853G>A) in the general population?

CUBN p.Arg3618Gln (c.10853G>A) is ultra-rare (popmax 0.0334%, amr) (gnomAD).

What do computational predictors say about CUBN p.Arg3618Gln (c.10853G>A)?

AlphaMissense predicts likely benign (score 0.0662) — an in-silico prediction, not a clinical call.

CUBN p.Arg3618Gln

c.10853G>A · rs780837561 · VCV939620

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0662 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

proteinuria, chronic benign

Computational evidence

Protein change
AlphaMissense	0.0662	likely benign
REVEL	0.027	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 -2.8
Regional constraint	o/e 1.00	unconstrained · MANE · 79 kb · p 0.98 · regional, not allelic
Overall
CADD	4.337	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 0.0334% Admixed American · 20/59,968 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00285% 46/1,613,458 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0334%	2,998
South Asian	0.00879%	11,381
African / African-American	0.00535%	18,704
Remaining individualsnot grpmax-eligible	0.0048%	20,823
Finnishnot grpmax-eligible	0.00156%	63,934
European (non-Finnish)	0.000848%	117,975

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.Arg3618Gln
Coding: c.10853G>A
MANE Select: NM_001081
dbSNP: rs780837561
Type: single nucleotide variant
Location: chr10:16824994 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3618: a UniProt-annotated variant site (in prochob); a UniProt-annotated variant site (in prochob; uncertain significance); the cub 27 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 p.Arg3618Ter 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.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-arg3618gln (accessed [today's date]).

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