Is CHRNA9 p.Pro148Ser (c.442C>T) pathogenic?

CHRNA9 p.Pro148Ser (c.442C>T) is classified Uncertain significance in CHRNA9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). AlphaMissense: likely pathogenic (0.8836); Ultra-rare (popmax 0.0156%, eas).

How common is CHRNA9 p.Pro148Ser (c.442C>T) in the general population?

CHRNA9 p.Pro148Ser (c.442C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about CHRNA9 p.Pro148Ser (c.442C>T)?

AlphaMissense predicts likely pathogenic (score 0.8836) — an in-silico prediction, not a clinical call.

CHRNA9 p.Pro148Ser

c.442C>T · VCV3492561

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8836 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8836	likely pathogenic
REVEL	0.897	moderately pathogenic-leaning
SaProt	LLR -11.07	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 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 19 kb · p 0.72 · regional, not allelic
Overall
CADD	25.8	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 0.0156% East Asian · 7/44,896 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00248% 40/1,614,072 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0384%	2,604
East Asiangrpmax	0.0156%	6,414
Admixed American	0.01%	10,001
African / African-American	0.004%	24,974

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CHRNA9
Protein: p.Pro148Ser
Coding: c.442C>T
MANE Select: NM_017581
Type: single nucleotide variant
Location: chr4:40348958 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.07 · 4 PDB
Residue 148: a β-strand

Full CHRNA9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRNA9 p.Ala22Asp Uncertain significance ★ ⚠ same type
CHRNA9 p.Ala263Pro Uncertain significance ★ ⚠ same type
CHRNA9 p.Ala305Thr Uncertain significance ★ ⚠ same type
CHRNA9 p.Ala31Thr Uncertain significance ★ ⚠ same type
CHRNA9 p.Arg138Gln Uncertain significance ★ ⚠ same type
CHRNA9 p.Arg138Pro Uncertain significance ★ ⚠ same type
CHRNA9 p.Arg138Trp Uncertain significance ★ ⚠ same type
CHRNA9 p.Arg19Thr 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/chrna9-p-pro148ser (accessed [today's date]).

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