Is CHRNB4 p.Pro405Leu (c.1214C>T) pathogenic?

CHRNB4 p.Pro405Leu (c.1214C>T) is classified Uncertain significance in CHRNB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.0893); Very rare (popmax 0.00667%, afr).

How common is CHRNB4 p.Pro405Leu (c.1214C>T) in the general population?

CHRNB4 p.Pro405Leu (c.1214C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about CHRNB4 p.Pro405Leu (c.1214C>T)?

AlphaMissense predicts likely benign (score 0.0893) — an in-silico prediction, not a clinical call.

CHRNB4 p.Pro405Leu

c.1214C>T · VCV4228517

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0893	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.6
Regional constraint	o/e 0.88	unconstrained · MANE · 4,276 bp · p 0.047 · regional, not allelic
Overall
CADD	8.934	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00667% African / African-American · 5/74,910 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.0013% 21/1,614,100 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,982
East Asian	0.00223%	44,898
Admixed American	0.00167%	60,006
European (non-Finnish)	0.0011%	90,774
South Asian	0.0011%	91,090

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: CHRNB4
Protein: p.Pro405Leu
Coding: c.1214C>T
MANE Select: NM_000750
Type: single nucleotide variant
Location: chr15:78629091 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.08 · 4 PDB

Full CHRNB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRNB4 c.*76T>C Benign ★★ same type
CHRNB4 p.Asn41Ser Benign ★★ ⚠ same type
CHRNB4 p.Ile240= Benign ★★ same type
CHRNB4 p.Thr375Ile Benign ★★ ⚠ same type
CHRNB4 p.Ala14Asp Uncertain significance ★ ⚠ same type
CHRNB4 p.Ala14Val Uncertain significance ★ ⚠ same type
CHRNB4 p.Ala393Thr Uncertain significance ★ ⚠ same type
CHRNB4 p.Ala395Thr 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/chrnb4-p-pro405leu (accessed [today's date]).

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