Is CNBD2 p.Arg139His (c.416G>A) pathogenic?

CNBD2 p.Arg139His (c.416G>A) is classified Uncertain significance in CNBD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-05). AlphaMissense: likely benign (0.2546); Ultra-rare (popmax 0.0401%, eas).

How common is CNBD2 p.Arg139His (c.416G>A) in the general population?

CNBD2 p.Arg139His (c.416G>A) is ultra-rare (popmax 0.0401%, eas) (gnomAD).

What do computational predictors say about CNBD2 p.Arg139His (c.416G>A)?

AlphaMissense predicts likely benign (score 0.2546) — an in-silico prediction, not a clinical call.

CNBD2 p.Arg139His

c.416G>A · rs138045142 · VCV2402572

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2546 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2546	likely benign
REVEL	0.66	pathogenic-leaning
SaProt	LLR -7.29	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 62 kb · p 0.4 · 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 0.0401% East Asian · 18/44,878 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00415% 67/1,614,164 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0401%	2,493
Middle Eastern	0.033%	3,029
South Asian	0.0231%	4,337
Remaining individualsnot grpmax-eligible	0.0048%	20,835
African / African-American	0.00266%	37,529
European (non-Finnish)	0.00178%	56,191

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.Arg139His
Coding: c.416G>A
MANE Select: NM_001365709
dbSNP: rs138045142
Type: single nucleotide variant
Location: chr20:35983990 (GRCh38)
Gene constraint: LOEUF 1.173 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.79
Residue 139: a binding site

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

Similar variants

CNBD2 p.Arg139Cys Uncertain significance ★ ⚠ same residue
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

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-arg139his (accessed [today's date]).

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