Is CHRNB4 p.Pro356Leu (c.1067C>T) pathogenic?

CHRNB4 p.Pro356Leu (c.1067C>T) is classified Likely benign in CHRNB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.0761); Ultra-rare (popmax 0.0165%, mid).

How common is CHRNB4 p.Pro356Leu (c.1067C>T) in the general population?

CHRNB4 p.Pro356Leu (c.1067C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CHRNB4 p.Pro356Leu (c.1067C>T)?

AlphaMissense predicts likely benign (score 0.0761) — an in-silico prediction, not a clinical call.

CHRNB4 p.Pro356Leu

c.1067C>T · VCV4228518

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0761 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0761	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -6.96	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 0.93	GERP -3.6
Regional constraint	o/e 0.88	unconstrained · MANE · 4,276 bp · p 0.047 · regional, not allelic
Overall
CADD	11.01	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 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00192% 31/1,613,410 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
Remaining individualsnot grpmax-eligible	0.0048%	20,828
South Asian	0.00329%	30,351
East Asian	0.00223%	44,856
European (non-Finnish)	0.00178%	56,170
Admixed American	0.00167%	59,992
African / African-American	0.00133%	75,018

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.Pro356Leu
Coding: c.1067C>T
MANE Select: NM_000750
Type: single nucleotide variant
Location: chr15:78629238 (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 p.Pro356= Benign ★ same residue
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

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-pro356leu (accessed [today's date]).

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