Is CUBN p.Pro949Ser (c.2845C>T) pathogenic?

CUBN p.Pro949Ser (c.2845C>T) is classified Uncertain significance in CUBN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.2586); Ultra-rare (popmax 0.0401%, afr); Associated with Inborn genetic diseases.

What condition is associated with CUBN p.Pro949Ser (c.2845C>T)?

CUBN p.Pro949Ser (c.2845C>T) is associated with Inborn genetic diseases, Imerslund-Grasbeck syndrome type 1 (ClinVar).

How common is CUBN p.Pro949Ser (c.2845C>T) in the general population?

CUBN p.Pro949Ser (c.2845C>T) is ultra-rare (popmax 0.0401%, afr) (gnomAD).

What do computational predictors say about CUBN p.Pro949Ser (c.2845C>T)?

AlphaMissense predicts likely benign (score 0.2586) — an in-silico prediction, not a clinical call.

CUBN p.Pro949Ser

c.2845C>T · rs376657324 · VCV2634353

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2586 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2586	likely benign
REVEL	0.366	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 84 kb · p 0.11 · regional, not allelic
Overall
CADD	26.4	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 0.0401% African / African-American · 30/74,894 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00229% 37/1,613,652 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0401%	2,496
Remaining individualsnot grpmax-eligible	0.008%	12,495
Admixed American	0.00167%	59,972
South Asian	0.0011%	91,080

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.Pro949Ser
Coding: c.2845C>T
MANE Select: NM_001081
dbSNP: rs376657324
Type: single nucleotide variant
Location: chr10:17068227 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 949: a disulfide bond; the cub 5 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Imerslund-Grasbeck syndrome type 1

Similar variants

CUBN p.Pro949Arg Uncertain significance ★ same residue
CUBN c.1230+1G>A Pathogenic/Likely pathogenic ★★ same condition
CUBN c.3672+2T>C 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.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-pro949ser (accessed [today's date]).

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