Is NPPA p.Val9Met (c.25G>A) pathogenic?

NPPA p.Val9Met (c.25G>A) is classified Conflicting classifications of pathogenicity in NPPA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-09). AlphaMissense: likely benign (0.0903); Ultra-rare (popmax 0.0653%, afr); Associated with atrial standstill 2.

What condition is associated with NPPA p.Val9Met (c.25G>A)?

NPPA p.Val9Met (c.25G>A) is associated with atrial standstill 2, atrial fibrillation, familial, 6 (ClinVar).

How common is NPPA p.Val9Met (c.25G>A) in the general population?

NPPA p.Val9Met (c.25G>A) is ultra-rare (popmax 0.0653%, afr) (gnomAD).

How is Isolated atrial standstill inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NPPA p.Val9Met (c.25G>A)?

AlphaMissense predicts likely benign (score 0.0903) — an in-silico prediction, not a clinical call.

NPPA p.Val9Met

c.25G>A · rs143419574 · VCV944170

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0903 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0653%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atrial standstill 2

Computational evidence

Protein change
AlphaMissense	0.0903	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -7.88	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 -7.8	GERP -3.1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,672 bp · p 0.33 · regional, not allelic
Overall
CADD	0.236	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 0.0653% African / African-American · 49/75,040 alleles

Filtering AF 0.0507% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0455%

Overall 0.00694% 112/1,614,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0653%	1,531
South Asian	0.00878%	11,384
Admixed American	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)	0.00415%	24,082

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.Val9Met
Coding: c.25G>A
MANE Select: NM_006172
dbSNP: rs143419574
Type: single nucleotide variant
Location: chr1:11847660 (GRCh38)
Gene constraint: LOEUF 1.301 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.11 · 13 PDB

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

Disease context

atrial standstill 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atrial fibrillation, familial, 6

For Isolated atrial standstill (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult

Similar variants

NPPA p.Ala35Thr Uncertain significance ★★ ⚠ same condition
NPPA p.Pro59Leu Uncertain significance ★★ ⚠ same condition
NPPA p.Leu125= Likely benign ★★ same condition
NPPA p.Ser142= Likely benign ★★ same condition
NPPA p.Thr8= Benign/Likely benign ★★ same condition
NPPA p.Val32Met Benign ★★ same condition
NPPA p.Arg107Gln Uncertain significance ★ ⚠ same condition
NPPA p.Arg116Lys 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/nppa-p-val9met (accessed [today's date]).

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