Is CHRNA2 p.Ala424Ser (c.1270G>T) pathogenic?

CHRNA2 p.Ala424Ser (c.1270G>T) is classified Uncertain significance in CHRNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely benign (0.0793); Very rare (popmax 8.56e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHRNA2 p.Ala424Ser (c.1270G>T)?

CHRNA2 p.Ala424Ser (c.1270G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHRNA2 p.Ala424Ser (c.1270G>T) in the general population?

CHRNA2 p.Ala424Ser (c.1270G>T) is very rare (popmax 8.56e-05%, nfe) (gnomAD).

What do computational predictors say about CHRNA2 p.Ala424Ser (c.1270G>T)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

CHRNA2 p.Ala424Ser

c.1270G>T · rs767138285 · VCV3144614

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.56e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.05	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 -0.013	GERP -1.5, phastCons 0.001
Regional constraint	o/e 1.05	unconstrained · MANE · 1,855 bp · p 0.38 · regional, not allelic
Overall
CADD	0.801	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 8.56e-05% European (non-Finnish) · 1/1,167,576 alleles

Overall 6.93e-05% 1/1,443,246 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: CHRNA2
Protein: p.Ala424Ser
Coding: c.1270G>T
MANE Select: NM_000742
dbSNP: rs767138285
Type: single nucleotide variant
Location: chr8:27463173 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 1 PDB

Full CHRNA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHRNA2 p.Ala424Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CHRNA2 p.Ala424= Likely benign ★ same residue
CHRNA2 p.Arg121Cys Uncertain significance ★★ ⚠ same condition
CHRNA2 p.Arg262Trp Uncertain significance ★★ ⚠ same condition
CHRNA2 p.Asp501Asn Uncertain significance ★★ ⚠ same condition
CHRNA2 p.Gly294Asp Uncertain significance ★★ ⚠ same condition
CHRNA2 p.Met362Leu Uncertain significance ★★ ⚠ same condition
CHRNA2 p.Pro76Arg Uncertain significance ★★ ⚠ same condition

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/chrna2-p-ala424ser (accessed [today's date]).

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