Is CBLC p.Thr197Ile (c.590C>T) pathogenic?

CBLC p.Thr197Ile (c.590C>T) is classified Uncertain significance in CBLC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-19). AlphaMissense: likely pathogenic (0.7841); Very rare (popmax 8.47e-05%, nfe).

How common is CBLC p.Thr197Ile (c.590C>T) in the general population?

CBLC p.Thr197Ile (c.590C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CBLC p.Thr197Ile (c.590C>T)?

AlphaMissense predicts likely pathogenic (score 0.7841) — an in-silico prediction, not a clinical call.

CBLC p.Thr197Ile

c.590C>T · rs2513641027 · VCV2218906

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7841 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7841	likely pathogenic · top 10% in CBLC
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -11.81	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 7.2	GERP 2.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.99 · regional, not allelic
Overall
CADD	25.0	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 8.47e-05% European (non-Finnish) · 1/1,180,006 alleles

Overall 6.84e-05% 1/1,461,252 alleles · very rare

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.Thr197Ile
Coding: c.590C>T
MANE Select: NM_012116
dbSNP: rs2513641027
Type: single nucleotide variant
Location: chr19:44781296 (GRCh38)
Gene constraint: LOEUF 1.058 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.85 · 7 PDB
Residue 197: the cbl-ptb domain; the 'ef-hand-like' region; an α-helix

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-thr197ile (accessed [today's date]).

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