Is CBLIF p.Ser46= (c.138G>T) pathogenic?

CBLIF p.Ser46= (c.138G>T) is classified Likely benign in CBLIF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). Very rare (popmax 0.00127%, nfe); Associated with hereditary intrinsic factor deficiency.

What condition is associated with CBLIF p.Ser46= (c.138G>T)?

CBLIF p.Ser46= (c.138G>T) is associated with hereditary intrinsic factor deficiency (ClinVar).

How common is CBLIF p.Ser46= (c.138G>T) in the general population?

CBLIF p.Ser46= (c.138G>T) is very rare (popmax 0.00127%, 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.

CBLIF p.Ser46=

c.138G>T · rs200472519 · VCV2963502

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Conditions

hereditary intrinsic factor deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.9
Overall
CADD	0.016	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00127% European (non-Finnish) · 15/1,179,630 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000992% 16/1,613,576 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,466
European (non-Finnish)grpmax	0.00127%	78,642

Remaining individuals 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: CBLIF
Protein: p.Ser46=
Coding: c.138G>T
MANE Select: NM_005142
dbSNP: rs200472519
Type: single nucleotide variant
Location: chr11:59843997 (GRCh38)
Gene constraint: LOEUF 0.865 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.69 · 2 PDB
Residue 46: a disulfide bond; a UniProt-annotated variant site (in ifd)

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.Ser46Leu Likely pathogenic ★★ ⚠ same residue
CBLIF c.79+1G>A 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-ser46 (accessed [today's date]).

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