Is CBLIF p.Pro125Arg (c.374C>G) pathogenic?

CBLIF p.Pro125Arg (c.374C>G) is classified Uncertain significance in CBLIF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely benign (0.0802); Rare (popmax 0.266%, mid).

How common is CBLIF p.Pro125Arg (c.374C>G) in the general population?

CBLIF p.Pro125Arg (c.374C>G) is rare (popmax 0.266%, mid) (gnomAD).

What do computational predictors say about CBLIF p.Pro125Arg (c.374C>G)?

AlphaMissense predicts likely benign (score 0.0802) — an in-silico prediction, not a clinical call.

CBLIF p.Pro125Arg

c.374C>G · rs868415065 · VCV3137991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0802 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.266%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0802	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -7.36	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 1.8	GERP -0.29, phastCons 0.013
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.16 · regional, not allelic
Overall
CADD	5.514	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 0.266% Middle Eastern · 16/6,026 alleles

Filtering AF 0.167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.136%

Overall 0.0013% 19/1,461,608 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.266%	377
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	8.48e-05%	1,179,860

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.Pro125Arg
Coding: c.374C>G
MANE Select: NM_005142
dbSNP: rs868415065
Type: single nucleotide variant
Location: chr11:59842580 (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

Similar variants

CBLIF p.Pro125Ser Uncertain significance ★★ ⚠ same residue
CBLIF c.79+1G>A Pathogenic ★★ same type
CBLIF p.Ser46Leu Likely pathogenic ★★ ⚠ same type
CBLIF p.Ala377Thr Uncertain significance ★★ ⚠ same type
CBLIF p.Ala377Val Uncertain significance ★★ ⚠ same type
CBLIF p.Arg104Gln Uncertain significance ★★ ⚠ same type
CBLIF p.Arg352Cys Uncertain significance ★★ ⚠ same type
CBLIF p.Arg352His Uncertain significance ★★ ⚠ same type

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-pro125arg (accessed [today's date]).

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