Is CHRNA9 p.Pro334Ser (c.1000C>T) pathogenic?

CHRNA9 p.Pro334Ser (c.1000C>T) is classified Uncertain significance in CHRNA9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-11). AlphaMissense: likely pathogenic (0.8961); Ultra-rare (popmax 0.0986%, mid).

How common is CHRNA9 p.Pro334Ser (c.1000C>T) in the general population?

CHRNA9 p.Pro334Ser (c.1000C>T) is ultra-rare (popmax 0.0986%, mid) (gnomAD).

What do computational predictors say about CHRNA9 p.Pro334Ser (c.1000C>T)?

AlphaMissense predicts likely pathogenic (score 0.8961) — an in-silico prediction, not a clinical call.

CHRNA9 p.Pro334Ser

c.1000C>T · rs138544578 · VCV2355197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8961 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0986%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8961	likely pathogenic
REVEL	0.715	pathogenic-leaning
SaProt	LLR -11.33	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 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 19 kb · p 0.72 · regional, not allelic
Overall
CADD	25.0	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 0.0986% Middle Eastern · 6/6,084 alleles

Filtering AF 0.0795% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0778%

Overall 0.0675% 1,090/1,614,088 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0986%	1,014
European (non-Finnish)	0.0839%	1,192
Remaining individualsnot grpmax-eligible	0.0608%	1,644
South Asian	0.0253%	3,960
African / African-American	0.0227%	4,408
Admixed American	0.0167%	6,000
Finnishnot grpmax-eligible	0.00937%	10,673

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.Pro334Ser
Coding: c.1000C>T
MANE Select: NM_017581
dbSNP: rs138544578
Type: single nucleotide variant
Location: chr4:40354080 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.07 · 4 PDB

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-pro334ser (accessed [today's date]).

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