Is NPPA p.Ter152Arg (c.454T>C) pathogenic?

NPPA p.Ter152Arg (c.454T>C) is classified Benign in NPPA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 40.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with atrial fibrillation, familial, 6.

What condition is associated with NPPA p.Ter152Arg (c.454T>C)?

NPPA p.Ter152Arg (c.454T>C) is associated with atrial fibrillation, familial, 6 (ClinVar).

How is Hereditary atrial fibrillation inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

NPPA p.Ter152Arg

Q: How common is NPPA p.Ter152Arg (c.454T>C) in the general population?

NPPA p.Ter152Arg (c.454T>C) is common (popmax 40.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.454T>C · rs5065 · VCV226855

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

stop-loss

predicted LoF

gnomAD v4.1

Common

common (popmax 40.8%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

atrial fibrillation, familial, 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	stop-loss	predicted loss-of-function
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.97	GERP -0.79, phastCons 0.95
Overall
CADD	12.66	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 40.8% African / African-American · 30,571/74,886 alleles

Filtering AF 40.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 40.3%

Overall 15.3% 246,218/1,613,250 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	40.8%	2
Middle Eastern	25%	4
South Asian	15.4%	6
Remaining individualsnot grpmax-eligible	15.3%	7
Amishnot grpmax-eligible	14.9%	7
European (non-Finnish)	14.9%	7
Ashkenazi Jewishnot grpmax-eligible	12.1%	8
Admixed American	10.6%	9
Finnishnot grpmax-eligible	7.56%	13
East Asian	0.991%	101

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: NPPA
Protein: p.Ter152Arg
Coding: c.454T>C
dbSNP: rs5065
Type: single nucleotide variant
Location: chr1:11846011 (GRCh38)

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

Disease context

atrial fibrillation, familial, 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary atrial fibrillation (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

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/nppa-p-ter152arg (accessed [today's date]).

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