Is NPPA p.Ser142= (c.426C>T) pathogenic?

NPPA p.Ser142= (c.426C>T) is classified Likely benign in NPPA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-16). Very rare (popmax 0.00452%, eas); Associated with atrial fibrillation, familial, 6.

What condition is associated with NPPA p.Ser142= (c.426C>T)?

NPPA p.Ser142= (c.426C>T) is associated with atrial fibrillation, familial, 6 (ClinVar).

How common is NPPA p.Ser142= (c.426C>T) in the general population?

NPPA p.Ser142= (c.426C>T) is very rare (popmax 0.00452%, eas) (gnomAD).

How is Hereditary atrial fibrillation inherited?

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

NPPA p.Ser142=

c.426C>T · rs747448548 · VCV917719

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00452%, eas)

Conditions

atrial fibrillation, familial, 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.9	GERP -3.1
Overall
CADD	3.601	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00452% East Asian · 2/44,254 alleles

Filtering AF 0.000749% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00028%

Overall 0.00103% 16/1,557,824 alleles · very rare exomes 14/1,405,746 · genomes 2/152,078 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00452%	22,127
Remaining individualsnot grpmax-eligible	0.00334%	29,945
African / African-American	0.00274%	36,523
South Asian	0.0024%	41,749
Admixed American	0.00193%	51,690
European (non-Finnish)	0.000608%	164,376

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.Ser142=
Coding: c.426C>T
MANE Select: NM_006172
dbSNP: rs747448548
Type: single nucleotide variant
Location: chr1:11847137 (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 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

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.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
NPPA p.Lys114Arg 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-ser142 (accessed [today's date]).

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