Is CNBD2 p.Leu291Pro (c.872T>C) pathogenic?

CNBD2 p.Leu291Pro (c.872T>C) is classified Uncertain significance in CNBD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely pathogenic (0.9696); Ultra-rare (popmax 0.0786%, afr).

How common is CNBD2 p.Leu291Pro (c.872T>C) in the general population?

CNBD2 p.Leu291Pro (c.872T>C) is ultra-rare (popmax 0.0786%, afr) (gnomAD).

What do computational predictors say about CNBD2 p.Leu291Pro (c.872T>C)?

AlphaMissense predicts likely pathogenic (score 0.9696) — an in-silico prediction, not a clinical call.

CNBD2 p.Leu291Pro

c.872T>C · rs34274439 · VCV2221153

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9696 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0786%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9696	likely pathogenic · top 1% in CNBD2
REVEL	0.457	indeterminate
SaProt	LLR -16.33	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 62 kb · p 0.4 · regional, not allelic
Overall
CADD	27.0	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 0.0786% African / African-American · 59/75,052 alleles

Filtering AF 0.0625% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0567%

Overall 0.00397% 64/1,614,070 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0786%	1,272
Admixed American	0.005%	20,007
Remaining individualsnot grpmax-eligible	0.0032%	31,248

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: CNBD2
Protein: p.Leu291Pro
Coding: c.872T>C
MANE Select: NM_001365709
dbSNP: rs34274439
Type: single nucleotide variant
Location: chr20:35995054 (GRCh38)
Gene constraint: LOEUF 1.173 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.79

Full CNBD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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CNBD2 p.Ala566Gly Uncertain significance ★ ⚠ same type
CNBD2 p.Ala566Thr Uncertain significance ★ ⚠ same type
CNBD2 p.Ala576Thr Uncertain significance ★ ⚠ same type
CNBD2 p.Ala88Thr Uncertain significance ★ ⚠ same type
CNBD2 p.Arg118Trp Uncertain significance ★ ⚠ same type
CNBD2 p.Arg133Cys Uncertain significance ★ ⚠ same type
CNBD2 p.Arg133His 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/cnbd2-p-leu291pro (accessed [today's date]).

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