Is CBLIF p.Pro394Ser (c.1180C>T) pathogenic?

CBLIF p.Pro394Ser (c.1180C>T) is classified Uncertain significance in CBLIF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-26). AlphaMissense: likely benign (0.1423); Very rare (popmax 0.00184%, nfe); Associated with hereditary intrinsic factor deficiency.

What condition is associated with CBLIF p.Pro394Ser (c.1180C>T)?

CBLIF p.Pro394Ser (c.1180C>T) is associated with hereditary intrinsic factor deficiency (ClinVar).

How common is CBLIF p.Pro394Ser (c.1180C>T) in the general population?

CBLIF p.Pro394Ser (c.1180C>T) is very rare (popmax 0.00184%, nfe) (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.Pro394Ser (c.1180C>T)?

AlphaMissense predicts likely benign (score 0.1423) — an in-silico prediction, not a clinical call.

CBLIF p.Pro394Ser

c.1180C>T · rs766270119 · VCV878167

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1423 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00184%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary intrinsic factor deficiency

Computational evidence

Protein change
AlphaMissense	0.1423	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -10.33	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.16 · regional, not allelic
Overall
CADD	25.0	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 0.00184% European (non-Finnish) · 19/1,033,000 alleles

Filtering AF 0.00118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000948%

Overall 0.00154% 20/1,300,654 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00184%	54,369
African / African-American	0.00139%	71,828

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.Pro394Ser
Coding: c.1180C>T
MANE Select: NM_005142
dbSNP: rs766270119
Type: single nucleotide variant
Location: chr11:59831690 (GRCh38)
Gene constraint: LOEUF 0.865 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.69 · 2 PDB
Residue 394: a binding site

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 p.Pro394fs Uncertain significance ★ same residue
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

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-pro394ser (accessed [today's date]).

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