Is CBLIF p.Pro355Arg (c.1064C>G) pathogenic?

CBLIF p.Pro355Arg (c.1064C>G) is classified Uncertain significance in CBLIF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-05). AlphaMissense: likely benign (0.1084); Rare (popmax 0.149%, afr); Associated with hereditary intrinsic factor deficiency.

What condition is associated with CBLIF p.Pro355Arg (c.1064C>G)?

CBLIF p.Pro355Arg (c.1064C>G) is associated with hereditary intrinsic factor deficiency (ClinVar).

How common is CBLIF p.Pro355Arg (c.1064C>G) in the general population?

CBLIF p.Pro355Arg (c.1064C>G) is rare (popmax 0.149%, afr) (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.Pro355Arg (c.1064C>G)?

AlphaMissense predicts likely benign (score 0.1084) — an in-silico prediction, not a clinical call.

CBLIF p.Pro355Arg

c.1064C>G · rs201871926 · VCV1005545

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1084 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary intrinsic factor deficiency

Computational evidence

Protein change
AlphaMissense	0.1084	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -8.60	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 5.8	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.16 · regional, not allelic
Overall
CADD	18.68	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 0.149% African / African-American · 112/74,984 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.118%

Overall 0.00776% 125/1,611,000 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.149%	670
Middle Eastern	0.0165%	6,056
Admixed American	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.00481%	20,795
South Asian	0.0022%	45,512
European (non-Finnish)	0.000255%	392,372

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.Pro355Arg
Coding: c.1064C>G
MANE Select: NM_005142
dbSNP: rs201871926
Type: single nucleotide variant
Location: chr11:59835817 (GRCh38)
Gene constraint: LOEUF 0.865 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.69 · 2 PDB
Residue 355: an α-helix

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

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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-pro355arg (accessed [today's date]).

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