Is CBLN3 p.Pro6Leu (c.17C>T) pathogenic?

CBLN3 p.Pro6Leu (c.17C>T) is classified Uncertain significance in CBLN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-26). AlphaMissense: likely benign (0.1256); Ultra-rare (popmax 0.0154%, amr).

How common is CBLN3 p.Pro6Leu (c.17C>T) in the general population?

CBLN3 p.Pro6Leu (c.17C>T) is ultra-rare (popmax 0.0154%, amr) (gnomAD).

What do computational predictors say about CBLN3 p.Pro6Leu (c.17C>T)?

AlphaMissense predicts likely benign (score 0.1256) — an in-silico prediction, not a clinical call.

CBLN3 p.Pro6Leu

c.17C>T · rs965025431 · VCV3138016

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1256 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1256	likely benign
REVEL	0.234	benign-leaning
SaProt	LLR -7.10	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 -8.5	GERP -3.9
Regional constraint	o/e 0.98	unconstrained · MANE · 1,262 bp · p 0.74 · regional, not allelic
Overall
CADD	0.198	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 0.0154% Admixed American · 7/45,602 alleles

Filtering AF 0.00716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00508%

Overall 0.000595% 9/1,512,842 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0154%	6,515
South Asian	0.00123%	81,250
European (non-Finnish)	8.89e-05%	1,124,439

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: CBLN3
Protein: p.Pro6Leu
Coding: c.17C>T
MANE Select: NM_001039771
dbSNP: rs965025431
Type: single nucleotide variant
Location: chr14:24429038 (GRCh38)
Gene constraint: LOEUF 1.271 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.67

Full CBLN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBLN3 p.Ala67Thr Uncertain significance ★ ⚠ same type
CBLN3 p.Ala76Glu Uncertain significance ★ ⚠ same type
CBLN3 p.Ala76Val Uncertain significance ★ ⚠ same type
CBLN3 p.Arg111Trp Uncertain significance ★ ⚠ same type
CBLN3 p.Arg136Cys Uncertain significance ★ ⚠ same type
CBLN3 p.Arg178Gln Uncertain significance ★ ⚠ same type
CBLN3 p.Arg184His Uncertain significance ★ ⚠ same type
CBLN3 p.Arg71Pro 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/cbln3-p-pro6leu (accessed [today's date]).

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