Is CHRNA6 p.Ser173Phe (c.518C>T) pathogenic?

CHRNA6 p.Ser173Phe (c.518C>T) is classified Uncertain significance in CHRNA6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). AlphaMissense: ambiguous (0.376); Very rare (popmax 0.00161%, nfe).

How common is CHRNA6 p.Ser173Phe (c.518C>T) in the general population?

CHRNA6 p.Ser173Phe (c.518C>T) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about CHRNA6 p.Ser173Phe (c.518C>T)?

AlphaMissense predicts ambiguous (score 0.376) — an in-silico prediction, not a clinical call.

CHRNA6 p.Ser173Phe

c.518C>T · VCV3833198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.376 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Computational evidence

Protein change
AlphaMissense	0.376	ambiguous
REVEL	0.61	indeterminate
SaProt	LLR -11.01	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 12 kb · p 0.41 · regional, not allelic
Overall
CADD	23.9	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 0.00161% European (non-Finnish) · 19/1,180,030 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00137% 20/1,461,864 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,107
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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: CHRNA6
Protein: p.Ser173Phe
Coding: c.518C>T
MANE Select: NM_004198
Type: single nucleotide variant
Location: chr8:42756681 (GRCh38)
Gene constraint: LOEUF 1.053 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.06 · 2 PDB
Residue 173: a β-strand

Full CHRNA6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRNA6 p.Ser266= Benign ★★ same type
CHRNA6 p.Arg109His Uncertain significance ★ ⚠ same type
CHRNA6 p.Arg330His Uncertain significance ★ ⚠ same type
CHRNA6 p.Arg376Gly Uncertain significance ★ ⚠ same type
CHRNA6 p.Arg96Cys Uncertain significance ★ ⚠ same type
CHRNA6 p.Asn402His Uncertain significance ★ ⚠ same type
CHRNA6 p.Asp119Asn Uncertain significance ★ ⚠ same type
CHRNA6 p.Asp129Asn 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/chrna6-p-ser173phe (accessed [today's date]).

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