Is CHRNB4 p.Val68Met (c.202G>A) pathogenic?

CHRNB4 p.Val68Met (c.202G>A) is classified Uncertain significance in CHRNB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-27). AlphaMissense: ambiguous (0.5272); Ultra-rare (popmax 0.0134%, eas).

How common is CHRNB4 p.Val68Met (c.202G>A) in the general population?

CHRNB4 p.Val68Met (c.202G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about CHRNB4 p.Val68Met (c.202G>A)?

AlphaMissense predicts ambiguous (score 0.5272) — an in-silico prediction, not a clinical call.

CHRNB4 p.Val68Met

c.202G>A · VCV3492592

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5272 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5272	ambiguous
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -10.26	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.74, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 10 kb · p 0.29 · regional, not allelic
Overall
CADD	26.6	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 · 6/44,886 alleles

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

Overall 0.00403% 65/1,613,708 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,481
European (non-Finnish)	0.00449%	22,263
Admixed American	0.00333%	30,006
South Asian	0.0022%	45,530
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00133%	75,056

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.Val68Met
Coding: c.202G>A
MANE Select: NM_000750
Type: single nucleotide variant
Location: chr15:78635441 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.08 · 4 PDB
Residue 68: 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-val68met (accessed [today's date]).

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