Is CUBN p.Pro2575Arg (c.7724C>G) pathogenic?

CUBN p.Pro2575Arg (c.7724C>G) is classified Benign in CUBN (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0876); Common (popmax 13.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Imerslund-Grasbeck syndrome type 1.

What condition is associated with CUBN p.Pro2575Arg (c.7724C>G)?

CUBN p.Pro2575Arg (c.7724C>G) is associated with Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome (ClinVar).

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.Pro2575Arg (c.7724C>G)?

AlphaMissense predicts likely benign (score 0.0876) — an in-silico prediction, not a clinical call.

CUBN p.Pro2575Arg

Q: How common is CUBN p.Pro2575Arg (c.7724C>G) in the general population?

CUBN p.Pro2575Arg (c.7724C>G) is common (popmax 13.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.7724C>G · rs3740168 · VCV299419

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0876 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 13.1%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Imerslund-Grasbeck syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0876	likely benign
REVEL	0.059	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 2.6	GERP -0.88, phastCons 0.1
Regional constraint	o/e 1.05	unconstrained · MANE · 84 kb · p 0.074 · regional, not allelic
Overall
CADD	7.558	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 13.1% East Asian · 5,856/44,848 alleles

Filtering AF 12.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.7%

Overall 2.58% 41,660/1,613,304 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	13.1%	8
Amishnot grpmax-eligible	9.87%	10
South Asian	9.23%	11
Admixed American	8.28%	12
Middle Eastern	5.2%	19
Remaining individualsnot grpmax-eligible	3.18%	31
European (non-Finnish)	1.57%	64
Ashkenazi Jewishnot grpmax-eligible	1.36%	73
Finnishnot grpmax-eligible	1.02%	99
African / African-American	0.628%	159

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.Pro2575Arg
Coding: c.7724C>G
MANE Select: NM_001081
dbSNP: rs3740168
Type: single nucleotide variant
Location: chr10:16906391 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2575: a disulfide bond; a UniProt-annotated variant site (in prochob); a UniProt-annotated variant site (in); the cub 19 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

For Imerslund-Gräsbeck syndrome (Orphanet):

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

Similar variants

CUBN p.Pro2575= 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-pro2575arg (accessed [today's date]).

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