Is CBLIF p.Pro125Ser (c.373C>T) pathogenic?

CBLIF p.Pro125Ser (c.373C>T) is classified Uncertain significance in CBLIF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-11). AlphaMissense: likely benign (0.0671); Ultra-rare (popmax 0.0226%, nfe); Associated with hereditary intrinsic factor deficiency.

What condition is associated with CBLIF p.Pro125Ser (c.373C>T)?

CBLIF p.Pro125Ser (c.373C>T) is associated with hereditary intrinsic factor deficiency (ClinVar).

How common is CBLIF p.Pro125Ser (c.373C>T) in the general population?

CBLIF p.Pro125Ser (c.373C>T) is ultra-rare (popmax 0.0226%, 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.Pro125Ser (c.373C>T)?

AlphaMissense predicts likely benign (score 0.0671) — an in-silico prediction, not a clinical call.

CBLIF p.Pro125Ser

c.373C>T · rs200473324 · VCV2043945

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0671 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0226%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary intrinsic factor deficiency

Computational evidence

Protein change
AlphaMissense	0.0671	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -6.49	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 0.66	GERP -1.9, phastCons 0.001
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.16 · regional, not allelic
Overall
CADD	2.161	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0226% European (non-Finnish) · 267/1,179,752 alleles

Filtering AF 0.0204% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0195%

Overall 0.0187% 302/1,613,652 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0544%	1,837
European (non-Finnish)grpmax	0.0226%	4,419
African / African-American	0.00133%	74,924

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.Pro125Ser
Coding: c.373C>T
MANE Select: NM_005142
dbSNP: rs200473324
Type: single nucleotide variant
Location: chr11:59842581 (GRCh38)
Gene constraint: LOEUF 0.865 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.69 · 2 PDB
Residue 125: a disulfide bond

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.Pro125Arg 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-pro125ser (accessed [today's date]).

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