Is NPPA p.Thr8= (c.24C>T) pathogenic?

NPPA p.Thr8= (c.24C>T) is classified Benign/Likely benign in NPPA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-06). Very rare (popmax 0.00891%, eas); Associated with atrial fibrillation, familial, 6.

What condition is associated with NPPA p.Thr8= (c.24C>T)?

NPPA p.Thr8= (c.24C>T) is associated with atrial fibrillation, familial, 6 (ClinVar).

How common is NPPA p.Thr8= (c.24C>T) in the general population?

NPPA p.Thr8= (c.24C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

How is Hereditary atrial fibrillation inherited?

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

NPPA p.Thr8=

c.24C>T · rs548535773 · VCV772530

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00891%, 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	<0.2	all four deltas below 0.2 · G>C here scores Δ0.70 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.3	GERP -3.1
Overall
CADD	0.16	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,872 alleles

Filtering AF 0.00503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00462%

Overall 0.00533% 86/1,614,096 alleles · very rare exomes 83/1,461,850 · genomes 3/152,246 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,417
East Asiangrpmax	0.00891%	11,218
European (non-Finnish)	0.00619%	16,165
Admixed American	0.00333%	30,016
South Asian	0.0011%	91,082

Remaining individuals 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.Thr8=
Coding: c.24C>T
MANE Select: NM_006172
dbSNP: rs548535773
Type: single nucleotide variant
Location: chr1:11847661 (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.Ser142= 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-thr8 (accessed [today's date]).

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