Is CHRNA7 p.Arg441Cys (c.1321C>T) pathogenic?

CHRNA7 p.Arg441Cys (c.1321C>T) is classified Uncertain significance in CHRNA7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). AlphaMissense: likely benign (0.1472); Very rare (popmax 0.00212%, amr).

How common is CHRNA7 p.Arg441Cys (c.1321C>T) in the general population?

CHRNA7 p.Arg441Cys (c.1321C>T) is very rare (popmax 0.00212%, amr) (gnomAD).

What do computational predictors say about CHRNA7 p.Arg441Cys (c.1321C>T)?

AlphaMissense predicts likely benign (score 0.1472) — an in-silico prediction, not a clinical call.

CHRNA7 p.Arg441Cys

c.1321C>T · VCV3492557

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1472 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1472	likely benign
REVEL	0.361	indeterminate
SaProt	LLR -10.27	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 364 bp · p 1e-35 · regional, not allelic
Overall
CADD	32.0	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 0.00212% Admixed American · 1/47,272 alleles

Filtering AF 0.00095% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000777%

Overall 0.00143% 19/1,325,004 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00212%	47,272
Remaining individualsnot grpmax-eligible	0.00176%	56,756
European (non-Finnish)	0.00156%	64,103

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: CHRNA7
Protein: p.Arg441Cys
Coding: c.1321C>T
MANE Select: NM_000746
Type: single nucleotide variant
Location: chr15:32168270 (GRCh38)
Gene constraint: LOEUF 1.064 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 51 PDB
Residue 441: an α-helix

Full CHRNA7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRNA7 p.Arg441His Uncertain significance ★ ⚠ same residue
CHRNA7 p.Asn381Asp Uncertain significance ★★ ⚠ same type
CHRNA7 p.Val374Met Uncertain significance ★★ ⚠ same type
CHRNA7 c.196-4G>T Likely benign ★★ same type
CHRNA7 c.240+113C>A Benign ★★ same type
CHRNA7 c.350+304G>A Likely benign ★★ same type
CHRNA7 c.55+77G>A Benign ★★ same type
CHRNA7 c.598+86C>T Benign ★★ 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/chrna7-p-arg441cys (accessed [today's date]).

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