Is CBLN3 p.Arg71Pro (c.212G>C) pathogenic?

CBLN3 p.Arg71Pro (c.212G>C) is classified Uncertain significance in CBLN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: ambiguous (0.3766); Ultra-rare (popmax 0.0169%, nfe).

How common is CBLN3 p.Arg71Pro (c.212G>C) in the general population?

CBLN3 p.Arg71Pro (c.212G>C) is ultra-rare (popmax 0.0169%, nfe) (gnomAD).

What do computational predictors say about CBLN3 p.Arg71Pro (c.212G>C)?

AlphaMissense predicts ambiguous (score 0.3766) — an in-silico prediction, not a clinical call.

CBLN3 p.Arg71Pro

c.212G>C · VCV3996136

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3766 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3766	ambiguous
REVEL	0.258	benign-leaning
SaProt	LLR -7.33	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,262 bp · p 0.74 · regional, not allelic
Overall
CADD	25.7	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 0.0169% European (non-Finnish) · 199/1,179,446 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0142%

Overall 0.0135% 217/1,612,430 alleles · ultra-rare exomes 204/1,460,378 · genomes 13/152,052 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0305%	3,281
European (non-Finnish)grpmax	0.0169%	5,927
Remaining individualsnot grpmax-eligible	0.0112%	8,920
Finnishnot grpmax-eligible	0.00315%	31,746

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg71Pro
Coding: c.212G>C
MANE Select: NM_001039771
Type: single nucleotide variant
Location: chr14:24428843 (GRCh38)
Gene constraint: LOEUF 1.271 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.67
Residue 71: the c1q domain

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.Asn187Ser 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-arg71pro (accessed [today's date]).

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