Is CBLC p.Pro365Leu (c.1094C>T) pathogenic?

CBLC p.Pro365Leu (c.1094C>T) is classified Uncertain significance in CBLC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-15). AlphaMissense: likely pathogenic (0.7607); Very rare (popmax 0.00224%, eas).

How common is CBLC p.Pro365Leu (c.1094C>T) in the general population?

CBLC p.Pro365Leu (c.1094C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about CBLC p.Pro365Leu (c.1094C>T)?

AlphaMissense predicts likely pathogenic (score 0.7607) — an in-silico prediction, not a clinical call.

CBLC p.Pro365Leu

c.1094C>T · rs971614881 · VCV2261229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7607 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7607	likely pathogenic
REVEL	0.818	moderately pathogenic-leaning
SaProt	LLR -14.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 2.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.99 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00224% East Asian · 1/44,674 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00155% 25/1,611,202 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,674
South Asian	0.0022%	45,463
European (non-Finnish)	0.00187%	53,598

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: CBLC
Protein: p.Pro365Leu
Coding: c.1094C>T
MANE Select: NM_012116
dbSNP: rs971614881
Type: single nucleotide variant
Location: chr19:44792471 (GRCh38)
Gene constraint: LOEUF 1.058 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.85 · 7 PDB
Residue 365: the 'interaction with ret' region

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

Similar variants

CBLC p.Ala122Ser Uncertain significance ★ ⚠ same type
CBLC p.Ala137Val Uncertain significance ★ ⚠ same type
CBLC p.Ala21Val Uncertain significance ★ ⚠ same type
CBLC p.Ala377Pro Uncertain significance ★ ⚠ same type
CBLC p.Ala398Val Uncertain significance ★ ⚠ same type
CBLC p.Ala433Ser Uncertain significance ★ ⚠ same type
CBLC p.Ala450Gly Uncertain significance ★ ⚠ same type
CBLC p.Ala465Val 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/cblc-p-pro365leu (accessed [today's date]).

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