Is CNBD2 p.Ile89Ser (c.266T>G) pathogenic?

CNBD2 p.Ile89Ser (c.266T>G) is classified Uncertain significance in CNBD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-18). AlphaMissense: ambiguous (0.3719); Ultra-rare (popmax 0.012%, afr).

How common is CNBD2 p.Ile89Ser (c.266T>G) in the general population?

CNBD2 p.Ile89Ser (c.266T>G) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about CNBD2 p.Ile89Ser (c.266T>G)?

AlphaMissense predicts ambiguous (score 0.3719) — an in-silico prediction, not a clinical call.

CNBD2 p.Ile89Ser

c.266T>G · VCV3834426

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3719 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3719	ambiguous
REVEL	0.273	benign-leaning
SaProt	LLR -8.34	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 62 kb · p 0.4 · regional, not allelic
Overall
CADD	22.5	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 0.012% African / African-American · 9/74,912 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.000682% 11/1,614,042 alleles · ultra-rare exomes 7/1,461,884 · genomes 4/152,158 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,324
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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.Ile89Ser
Coding: c.266T>G
MANE Select: NM_001365709
Type: single nucleotide variant
Location: chr20:35980481 (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

CNBD2 p.Ala121Thr Uncertain significance ★ ⚠ same type
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-ile89ser (accessed [today's date]).

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