Is CNBD2 p.Arg141His (c.422G>A) pathogenic?

CNBD2 p.Arg141His (c.422G>A) is classified Uncertain significance in CNBD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-20). AlphaMissense: ambiguous (0.3516); Ultra-rare (popmax 0.0134%, eas).

How common is CNBD2 p.Arg141His (c.422G>A) in the general population?

CNBD2 p.Arg141His (c.422G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about CNBD2 p.Arg141His (c.422G>A)?

AlphaMissense predicts ambiguous (score 0.3516) — an in-silico prediction, not a clinical call.

CNBD2 p.Arg141His

c.422G>A · rs144274307 · VCV2353442

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3516 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3516	ambiguous
REVEL	0.691	pathogenic-leaning
SaProt	LLR -9.26	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
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	29.8	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 0.0134% East Asian · 6/44,898 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000743% 12/1,614,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,483
Finnishnot grpmax-eligible	0.00156%	64,038
African / African-American	0.00133%	74,916
South Asian	0.0011%	91,088
European (non-Finnish)	0.000254%	393,342

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.Arg141His
Coding: c.422G>A
MANE Select: NM_001365709
dbSNP: rs144274307
Type: single nucleotide variant
Location: chr20:35983996 (GRCh38)
Gene constraint: LOEUF 1.173 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.79
Residue 141: a binding site

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

Similar variants

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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-arg141his (accessed [today's date]).

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