Is CHRNB4 p.Phe160Leu (c.480T>G) pathogenic?

CHRNB4 p.Phe160Leu (c.480T>G) is classified Uncertain significance in CHRNB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.991); Very rare (popmax 0.000169%, nfe).

How common is CHRNB4 p.Phe160Leu (c.480T>G) in the general population?

CHRNB4 p.Phe160Leu (c.480T>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CHRNB4 p.Phe160Leu (c.480T>G)?

AlphaMissense predicts likely pathogenic (score 0.991) — an in-silico prediction, not a clinical call.

CHRNB4 p.Phe160Leu

c.480T>G · VCV4228521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.991	likely pathogenic · top 2% in CHRNB4
REVEL	0.897	moderately pathogenic-leaning
SaProt	LLR -12.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.68	GERP -3.9, phastCons 0.99
Regional constraint	o/e 0.76	unconstrained · MANE · 1,499 bp · p 0.0018 · regional, not allelic
Overall
CADD	21.5	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 0.000169% European (non-Finnish) · 2/1,180,002 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,866 alleles · very rare

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.Phe160Leu
Coding: c.480T>G
MANE Select: NM_000750
Type: single nucleotide variant
Location: chr15:78629825 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.08 · 4 PDB
Residue 160: a disulfide bond; a β-strand

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-phe160leu (accessed [today's date]).

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