Is CBLN3 p.Pro119Arg (c.356C>G) pathogenic?

CBLN3 p.Pro119Arg (c.356C>G) is classified Uncertain significance in CBLN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-24). AlphaMissense: ambiguous (0.516); Ultra-rare (popmax 0.0132%, sas).

How common is CBLN3 p.Pro119Arg (c.356C>G) in the general population?

CBLN3 p.Pro119Arg (c.356C>G) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about CBLN3 p.Pro119Arg (c.356C>G)?

AlphaMissense predicts ambiguous (score 0.516) — an in-silico prediction, not a clinical call.

CBLN3 p.Pro119Arg

c.356C>G · rs146562304 · VCV2520770

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.516 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Computational evidence

Protein change
AlphaMissense	0.516	ambiguous
REVEL	0.613	indeterminate
SaProt	LLR -9.94	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,262 bp · p 0.74 · regional, not allelic
Overall
CADD	29.1	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 0.0132% South Asian · 12/91,084 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00118% 19/1,613,976 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,590
Remaining individualsnot grpmax-eligible	0.0064%	15,624
African / African-American	0.004%	25,007

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.Pro119Arg
Coding: c.356C>G
MANE Select: NM_001039771
dbSNP: rs146562304
Type: single nucleotide variant
Location: chr14:24428350 (GRCh38)
Gene constraint: LOEUF 1.271 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.67
Residue 119: the c1q domain; the 'necessary for interaction with cbln3, and homotrimerization' region

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

Similar variants

CBLN3 p.Pro119Leu Uncertain significance ★ ⚠ same residue
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

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-pro119arg (accessed [today's date]).

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