Is CUBN p.Phe253Ser (c.758T>C) pathogenic?

CUBN p.Phe253Ser (c.758T>C) is classified Benign in CUBN (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0626); Common (popmax 88.2%, mid) — too common for a highly-penetrant pathogenic allele; Associated with Imerslund-Grasbeck syndrome type 1.

What condition is associated with CUBN p.Phe253Ser (c.758T>C)?

CUBN p.Phe253Ser (c.758T>C) 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.Phe253Ser (c.758T>C)?

AlphaMissense predicts likely benign (score 0.0626) — an in-silico prediction, not a clinical call.

CUBN p.Phe253Ser

Q: How common is CUBN p.Phe253Ser (c.758T>C) in the general population?

CUBN p.Phe253Ser (c.758T>C) is common (popmax 88.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.758T>C · rs1801222 · VCV299538

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0626 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 88.2%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Imerslund-Grasbeck syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0626	likely benign
REVEL	0.209	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.7	GERP -1.3, phastCons 0.6
Regional constraint	o/e 1.04	unconstrained · MANE · 84 kb · p 0.11 · regional, not allelic
Overall
CADD	9.22	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 88.2% Middle Eastern · 5,349/6,062 alleles

Filtering AF 86.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 85.5%

Overall 67.7% 1,092,138/1,612,932 alleles · common exomes 981,670/1,460,846 · genomes 110,468/152,086 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	88.2%	1
South Asian	83.7%	1
East Asian	82.5%	1
African / African-American	80.7%	1
Admixed American	78.9%	1
Ashkenazi Jewishnot grpmax-eligible	76.8%	1
Remaining individualsnot grpmax-eligible	71.1%	1
Finnishnot grpmax-eligible	68.8%	1
European (non-Finnish)	64%	2
Amishnot grpmax-eligible	54.8%	2

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.Phe253Ser
Coding: c.758T>C
MANE Select: NM_001081
dbSNP: rs1801222
Type: single nucleotide variant
Location: chr10:17114152 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 253: a UniProt-annotated variant site (in)

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-phe253ser (accessed [today's date]).

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