# NM_153240.5(NPHP3):c.2171G>A (p.Arg724His)

https://sugi.bio/variant/nphp3-p-arg724his

## Summary

**NPHP3 p.Arg724His (c.2171G>A)** is classified **Uncertain significance** in NPHP3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-09-01). AlphaMissense: likely benign (0.0794); Ultra-rare (popmax 0.0201%, eas); Associated with nephronophthisis.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1064797063 · 3 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0201%, eas)

## For patients & families {#patients}

This is a change in the NPHP3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to nephronophthisis.

*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 recessive |
| Age of onset (of this condition) | Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Finland) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | NPHP3 is a diagnostic-grade gene on 15 Genomics England panels |

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

- Renal insufficiency — Frequent (79-30%)
- Anemia — Frequent (79-30%)
- Abnormality of retinal pigmentation — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000206/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NPHP3](https://sugi.bio/atlas/gene/NPHP3/) |
| Protein change (HGVS p.) | p.Arg724His |
| Coding change (HGVS c.) | c.2171G>A |
| MANE Select transcript | [NM_153240](https://www.ncbi.nlm.nih.gov/nuccore/NM_153240) |
| dbSNP | [rs1064797063](https://www.ncbi.nlm.nih.gov/snp/rs1064797063/) |
| Variant type | single nucleotide variant |
| Location | chr3:132696731-132696731 (GRCh38) |
| ClinVar | [VCV424601](https://www.ncbi.nlm.nih.gov/clinvar/variation/424601/) |

**All HGVS expressions:** `NC_000003.11:g.132415575C>T`, `NC_000003.12:g.132696731C>T`, `NG_008130.2:g.30702G>A`, `NM_153240.5:c.2171G>A`, `NR_037804.1:n.2177G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0794)
- REVEL 0.093 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.77 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.065, GERP -0.814, phastCons 0.501 — weakly conserved position
- CADD: **PHRED 22.5**. 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.*
- Regional missense constraint: **o/e 1.01** across the covering region of the MANE Select transcript (132,692,806–132,722,316), spanning 29,510 bp. Chi-square p 0.87. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.24 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Pangolin: Δ**0.37** (loss), gain 0.18 / loss 0.37. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0201%** (eas) · FAF95 0.0104% · FAF99 0.00779% · 9/44,874 in the highest group · 20/1,613,582 alleles overall — ultra-rare (popmax 0.0201%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0201% | 4,986 |
| South Asian | 0.0011% | 91,060 |
| European (non-Finnish) | 0.000848% | 117,949 |

*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}

**NPHP3** population constraint: LOEUF 0.873, pLI 1.4471e-21, missense-Z 0.91316. *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):

- **nephronophthisis** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.59, 9% of residues very-high.

**1 experimental structure(s)** (PDB): [5L7K](https://www.rcsb.org/structure/5L7K).

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

*Describes the biological roles of NPHP3 (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.*


### Pathways affected {#pathways}

NPHP3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Trafficking of myristoylated proteins to the cilium](https://reactome.org/content/detail/R-HSA-5624138) | curated |

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

**Biological process:** kidney development, heart looping, atrial septum development, determination of left/right symmetry, lung development, determination of pancreatic left/right asymmetry.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-09-01.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2017–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-01 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-01 |

## Associated conditions {#conditions}

[nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/).

**Reported phenotype names (ClinVar):** Nephronophthisis, not provided, Juvenile Nephronophthisis, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related NPHP3 variant pages (same residue, condition, or type): [NPHP3 c.1985+1G>A](/variant/nphp3-c-1985-plus-1g-a), [NPHP3 c.3201+1G>T](/variant/nphp3-c-3201-plus-1g-t), [NPHP3 c.393+1G>C](/variant/nphp3-c-393-plus-1g-c), [NPHP3 c.958-2A>G](/variant/nphp3-c-958-minus-2a-g), [NPHP3 p.Arg1125Ter](/variant/nphp3-p-arg1125ter), [NPHP3 p.Arg1259Ter](/variant/nphp3-p-arg1259ter), [NPHP3 p.Arg142Ter](/variant/nphp3-p-arg142ter), [NPHP3 p.Arg577Ter](/variant/nphp3-p-arg577ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 424601). 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.*