Is CBLC p.Cys168Ser (c.503G>C) pathogenic?

CBLC p.Cys168Ser (c.503G>C) is classified Uncertain significance in CBLC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: ambiguous (0.4268); Very rare (popmax 0.00221%, nfe).

How common is CBLC p.Cys168Ser (c.503G>C) in the general population?

CBLC p.Cys168Ser (c.503G>C) is very rare (popmax 0.00221%, nfe) (gnomAD).

What do computational predictors say about CBLC p.Cys168Ser (c.503G>C)?

AlphaMissense predicts ambiguous (score 0.4268) — an in-silico prediction, not a clinical call.

CBLC p.Cys168Ser

c.503G>C · VCV4219966

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4268 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4268	ambiguous
REVEL	0.514	indeterminate
SaProt	LLR -3.71	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.1, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 3,282 bp · p 0.0054 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00221% European (non-Finnish) · 26/1,178,246 alleles

Filtering AF 0.00154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00168% 27/1,610,514 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00221%	45,317
Remaining individualsnot grpmax-eligible	0.0016%	62,310

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.Cys168Ser
Coding: c.503G>C
MANE Select: NM_012116
Type: single nucleotide variant
Location: chr19:44781209 (GRCh38)
Gene constraint: LOEUF 1.058 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.85 · 7 PDB
Residue 168: the cbl-ptb domain; the 'ef-hand-like' region; a β-strand

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-cys168ser (accessed [today's date]).

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