# NM_006172.4(NPPA):c.198G>A (p.Pro66=)

https://sugi.bio/variant/nppa-p-pro66

## Summary

**NPPA p.Pro66= (c.198G>A)** is classified **Likely benign** in NPPA (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-01). Rare (popmax 0.164%, sas); Associated with atrial fibrillation, familial, 6.

**At a glance:** Likely benign · review: Single submitter · rsID rs767807184 · 1 submitter · 1 linked condition · rare (popmax 0.164%, sas)

## For patients & families {#patients}

This is a change in the NPPA gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to atrial fibrillation, familial, 6.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult, Elderly |

**Commonly reported features of Hereditary atrial fibrillation** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Syncope — Frequent (79-30%)
- Palpitations — Frequent (79-30%)
- Dyspnea — Frequent (79-30%)
- Vertigo — Frequent (79-30%)
- Exercise intolerance — Frequent (79-30%)
- Atrial fibrillation — Frequent (79-30%)
- Fatigue — Frequent (79-30%)
- Chest pain — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015544/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NPPA](https://sugi.bio/atlas/gene/NPPA/) |
| Protein change (HGVS p.) | p.Pro66= |
| Coding change (HGVS c.) | c.198G>A |
| MANE Select transcript | [NM_006172](https://www.ncbi.nlm.nih.gov/nuccore/NM_006172) |
| dbSNP | [rs767807184](https://www.ncbi.nlm.nih.gov/snp/rs767807184/) |
| Variant type | single nucleotide variant |
| Location | chr1:11847365-11847365 (GRCh38) |
| ClinVar | [VCV469606](https://www.ncbi.nlm.nih.gov/clinvar/variation/469606/) |

**All HGVS expressions:** `LRG_751:g.5419G>A`, `LRG_751t1:c.198G>A`, `NC_000001.10:g.11907422C>T`, `NC_000001.11:g.11847365C>T`, `NG_012926.1:g.5419G>A`, `NG_065183.1:g.647C>T`, `NM_006172.4:c.198G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 4.04, GERP 1.71, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.81**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.164%** (sas) · FAF95 0.142% · FAF99 0.134% · 149/91,076 in the highest group · 241/1,613,912 alleles overall — rare (popmax 0.164%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.164% | 611 |
| Admixed American | 0.03% | 3,333 |
| Remaining individuals (not grpmax-eligible) | 0.0208% | 4,807 |
| Middle Eastern | 0.0165% | 6,062 |
| European (non-Finnish) | 0.00509% | 19,665 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**NPPA** population constraint: LOEUF 1.301, pLI 0.0013218, missense-Z -0.2232. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **dilated cardiomyopathy** — No Known Disease Relationship (AR)

## Protein context {#protein}

Residue **66** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 64.11, 12% of residues very-high.

**13 experimental structure(s)** (PDB): [1ANP](https://www.rcsb.org/structure/1ANP), [1YK0](https://www.rcsb.org/structure/1YK0), [3N57](https://www.rcsb.org/structure/3N57), [7BRH](https://www.rcsb.org/structure/7BRH), [7BRJ](https://www.rcsb.org/structure/7BRJ), [7BRK](https://www.rcsb.org/structure/7BRK) — incl. mutant structure 1ANP.

## What this gene does {#gene-function}

*Describes the biological roles of NPPA (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** NPPA's established molecular role includes signaling receptor binding. p.Pro66= falls in the disordered region.


### Pathways affected {#pathways}

NPPA participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Amyloid fiber formation](https://reactome.org/content/detail/R-HSA-977225) | curated |
| [Physiological factors](https://reactome.org/content/detail/R-HSA-5578768) | curated |
| [YAP1- and WWTR1 (TAZ)-stimulated gene expression](https://reactome.org/content/detail/R-HSA-2032785) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** signaling receptor binding, neuropeptide hormone activity, hormone receptor binding, neuropeptide receptor binding.

**Biological process:** cGMP biosynthetic process, protein folding, receptor guanylyl cyclase signaling pathway, neuropeptide signaling pathway, regulation of blood pressure, positive regulation of heart rate.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-01 |

## Associated conditions {#conditions}

[atrial fibrillation, familial, 6](https://sugi.bio/atlas/disease/atrial-fibrillation-familial-6/).

**Reported phenotype names (ClinVar):** Atrial fibrillation, familial, 6.

## Similar variants {#similar}

Related NPPA variant pages (same residue, condition, or type): [NPPA p.Ala35Thr](/variant/nppa-p-ala35thr), [NPPA p.Pro59Leu](/variant/nppa-p-pro59leu), [NPPA p.Leu125=](/variant/nppa-p-leu125), [NPPA p.Ser142=](/variant/nppa-p-ser142), [NPPA p.Thr8=](/variant/nppa-p-thr8), [NPPA p.Val32Met](/variant/nppa-p-val32met), [NPPA p.Arg107Gln](/variant/nppa-p-arg107gln), [NPPA p.Arg116Lys](/variant/nppa-p-arg116lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 469606). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*