Is CUBN p.Pro1975Leu (c.5924C>T) pathogenic?

CUBN p.Pro1975Leu (c.5924C>T) is classified Benign/Likely benign in CUBN (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0917); Low-frequency (popmax 2.97%, amr); Associated with Imerslund-Grasbeck syndrome type 1.

What condition is associated with CUBN p.Pro1975Leu (c.5924C>T)?

CUBN p.Pro1975Leu (c.5924C>T) is associated with Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome (ClinVar).

How common is CUBN p.Pro1975Leu (c.5924C>T) in the general population?

CUBN p.Pro1975Leu (c.5924C>T) is low-frequency (popmax 2.97%, 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.Pro1975Leu (c.5924C>T)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

CUBN p.Pro1975Leu

c.5924C>T · rs41289303 · VCV299450

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.97%, amr)

Conditions

Imerslund-Grasbeck syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.341	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 84 kb · p 0.074 · regional, not allelic
Overall
CADD	25.3	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 2.97% Admixed American · 1,784/59,984 alleles

Filtering AF 2.86% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.81%

Overall 1.02% 16,381/1,613,178 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	5.29%	19
Admixed Americangrpmax	2.97%	34
Amishnot grpmax-eligible	2.19%	46
European (non-Finnish)	0.883%	113
Remaining individualsnot grpmax-eligible	0.676%	148
Ashkenazi Jewishnot grpmax-eligible	0.602%	166
African / African-American	0.125%	797
South Asian	0.0868%	1,153
Middle Eastern	0.0661%	1,514

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1975Leu
Coding: c.5924C>T
MANE Select: NM_001081
dbSNP: rs41289303
Type: single nucleotide variant
Location: chr10:16937594 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1975: a UniProt-annotated variant site (in prochob)

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 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-pro1975leu (accessed [today's date]).

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