Is NPPA p.Ser64Arg (c.190A>C) pathogenic?

NPPA p.Ser64Arg (c.190A>C) is classified Benign/Likely benign in NPPA (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.1161); Rare (popmax 0.285%, nfe); Associated with atrial fibrillation, familial, 6.

What condition is associated with NPPA p.Ser64Arg (c.190A>C)?

NPPA p.Ser64Arg (c.190A>C) is associated with atrial fibrillation, familial, 6, atrial standstill 2 (ClinVar).

How common is NPPA p.Ser64Arg (c.190A>C) in the general population?

NPPA p.Ser64Arg (c.190A>C) is rare (popmax 0.285%, nfe) (gnomAD).

How is Hereditary atrial fibrillation inherited?

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

What do computational predictors say about NPPA p.Ser64Arg (c.190A>C)?

AlphaMissense predicts likely benign (score 0.1161) — an in-silico prediction, not a clinical call.

NPPA p.Ser64Arg

c.190A>C · rs61757261 · VCV126847

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1161 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.285%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atrial fibrillation, familial, 6

Computational evidence

Protein change
AlphaMissense	0.1161	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.4	GERP -0.37, phastCons 0.1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,672 bp · p 0.33 · regional, not allelic
Overall
CADD	7.723	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 0.285% European (non-Finnish) · 3,368/1,179,964 alleles

Filtering AF 0.277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.274%

Overall 0.247% 3,991/1,614,004 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.628%	159
European (non-Finnish)grpmax	0.285%	350
Middle Eastern	0.231%	433
Remaining individualsnot grpmax-eligible	0.229%	437
Admixed American	0.188%	531
South Asian	0.0988%	1,012
Finnishnot grpmax-eligible	0.0579%	1,728
African / African-American	0.052%	1,925
East Asian	0.00223%	44,880

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser64Arg
Coding: c.190A>C
dbSNP: rs61757261
Type: single nucleotide variant
Location: chr1:11847373 (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

Also linked: atrial standstill 2

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-ser64arg (accessed [today's date]).

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