Is CHRNE p.Arg352Ser (c.1054C>A) pathogenic?

CHRNE p.Arg352Ser (c.1054C>A) is classified Uncertain significance in CHRNE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-09). AlphaMissense: likely benign (0.1187); Very rare (popmax 0.000262%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHRNE p.Arg352Ser (c.1054C>A)?

CHRNE p.Arg352Ser (c.1054C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CHRNE p.Arg352Ser (c.1054C>A) in the general population?

CHRNE p.Arg352Ser (c.1054C>A) is very rare (popmax 0.000262%, nfe) (gnomAD).

What do computational predictors say about CHRNE p.Arg352Ser (c.1054C>A)?

AlphaMissense predicts likely benign (score 0.1187) — an in-silico prediction, not a clinical call.

CHRNE p.Arg352Ser

c.1054C>A · VCV3492601

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000262%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1187	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -7.36	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 2.5	GERP 0.63, phastCons 0.11
Regional constraint	o/e 1.15	unconstrained · MANE · 4,324 bp · p 7.4e-05 · regional, not allelic
Overall
CADD	18.65	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 0.000262% European (non-Finnish) · 3/1,146,010 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000217% 3/1,382,288 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: CHRNE
Protein: p.Arg352Ser
Coding: c.1054C>A
MANE Select: NM_000080
Type: single nucleotide variant
Location: chr17:4899363 (GRCh38)
Gene constraint: LOEUF 1.298 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 25 PDB
Residue 352: an α-helix

Full CHRNE 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

CHRNE p.Arg352= Likely benign ★★ same residue
CHRNE p.Arg352His Uncertain significance ★ ⚠ same residue
CHRNE p.Ala362Asp Uncertain significance ★★ ⚠ same condition
CHRNE p.Ala372Val Uncertain significance ★★ ⚠ same condition
CHRNE p.Arg380Cys Uncertain significance ★★ ⚠ same condition
CHRNE p.Arg421Cys Uncertain significance ★★ ⚠ same condition
CHRNE p.Arg421His Uncertain significance ★★ ⚠ same condition
CHRNE p.Arg449His 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/chrne-p-arg352ser (accessed [today's date]).

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