Is CBLIF p.Pro304Ser (c.910C>T) pathogenic?

CBLIF p.Pro304Ser (c.910C>T) is classified Conflicting classifications of pathogenicity in CBLIF (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.077); Rare (popmax 0.528%, mid); Associated with hereditary intrinsic factor deficiency.

What condition is associated with CBLIF p.Pro304Ser (c.910C>T)?

CBLIF p.Pro304Ser (c.910C>T) is associated with hereditary intrinsic factor deficiency (ClinVar).

How common is CBLIF p.Pro304Ser (c.910C>T) in the general population?

CBLIF p.Pro304Ser (c.910C>T) is rare (popmax 0.528%, mid) (gnomAD).

How is Congenital intrinsic factor deficiency inherited?

Typically Autosomal recessive, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CBLIF p.Pro304Ser (c.910C>T)?

AlphaMissense predicts likely benign (score 0.077) — an in-silico prediction, not a clinical call.

CBLIF p.Pro304Ser

c.910C>T · rs150926439 · VCV305032

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.077 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.528%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary intrinsic factor deficiency

Computational evidence

Protein change
AlphaMissense	0.077	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.57	GERP -3.7, phastCons 0.008
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.16 · regional, not allelic
Overall
CADD	3.162	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 0.528% Middle Eastern · 32/6,062 alleles

Filtering AF 0.384% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.335%

Overall 0.112% 1,802/1,614,168 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.528%	189
Ashkenazi Jewishnot grpmax-eligible	0.456%	219
Remaining individualsnot grpmax-eligible	0.163%	613
European (non-Finnish)	0.118%	848
Amishnot grpmax-eligible	0.11%	912
South Asian	0.0955%	1,047
Admixed American	0.0566%	1,766
African / African-American	0.024%	4,169
Finnishnot grpmax-eligible	0.00312%	32,019

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: CBLIF
Protein: p.Pro304Ser
Coding: c.910C>T
MANE Select: NM_005142
dbSNP: rs150926439
Type: single nucleotide variant
Location: chr11:59835971 (GRCh38)
Gene constraint: LOEUF 0.865 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.69 · 2 PDB

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

Disease context

hereditary intrinsic factor deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital intrinsic factor deficiency (Orphanet):

Inheritance: Autosomal recessive, Not applicable
Onset: Childhood

Similar variants

CBLIF c.79+1G>A Pathogenic ★★ same condition
CBLIF p.Ser46Leu Likely pathogenic ★★ ⚠ same condition
CBLIF p.Ala377Thr Uncertain significance ★★ ⚠ same condition
CBLIF p.Ala377Val Uncertain significance ★★ ⚠ same condition
CBLIF p.Arg104Gln Uncertain significance ★★ ⚠ same condition
CBLIF p.Arg352Cys Uncertain significance ★★ ⚠ same condition
CBLIF p.Arg352His Uncertain significance ★★ ⚠ same condition
CBLIF p.Gln351Glu Uncertain significance ★★ ⚠ 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/cblif-p-pro304ser (accessed [today's date]).

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