# NM_153240.5(NPHP3):c.152C>T (p.Ala51Val)

https://sugi.bio/variant/nphp3-p-ala51val

## Summary

**NPHP3 p.Ala51Val (c.152C>T)** is classified **Conflicting classifications of pathogenicity** in NPHP3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.119); Ultra-rare (popmax 0.0774%, afr); Associated with nephronophthisis.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs577583077 · 4 submitters · 4 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0774%, afr)

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## For patients & families {#patients}

This is a change in the NPHP3 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 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 |

**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.Ala51Val |
| Coding change (HGVS c.) | c.152C>T |
| MANE Select transcript | [NM_153240](https://www.ncbi.nlm.nih.gov/nuccore/NM_153240) |
| dbSNP | [rs577583077](https://www.ncbi.nlm.nih.gov/snp/rs577583077/) |
| Variant type | single nucleotide variant |
| Location | chr3:132722204-132722204 (GRCh38) |
| ClinVar | [VCV843396](https://www.ncbi.nlm.nih.gov/clinvar/variation/843396/) |

**All HGVS expressions:** `NC_000003.11:g.132441048G>A`, `NC_000003.12:g.132722204G>A`, `NG_008130.2:g.5229C>T`, `NM_153240.5:c.152C>T`, `NR_002811.2:n.455G>A`, `NR_037804.1:n.256C>T`, `NR_152743.1:n.455G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.119)
- REVEL 0.134 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.951 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.562, GERP 0.381, phastCons 0.902 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 11.68**. 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: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.0774%** (afr) · FAF95 0.0609% · FAF99 0.055% · 54/69,780 in the highest group · 118/1,510,812 alleles overall — ultra-rare (popmax 0.0774%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0774% | 1,292 |
| East Asian | 0.019% | 5,269 |
| Remaining individuals (not grpmax-eligible) | 0.0137% | 7,312 |
| Admixed American | 0.0128% | 7,812 |
| South Asian | 0.00496% | 20,157 |
| European (non-Finnish) | 0.00334% | 29,966 |
| Finnish (not grpmax-eligible) | 0.00216% | 46,386 |

*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.*

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-16.

**Submitter consensus:** conflicting (2 Likely benign, 2 Uncertain significance).

**Submission history:** 3 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-16 |
| Breakthrough Genomics, Breakthrough Genomics | Uncertain significance | criteria provided, single submitter | not provided |  |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-14 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-28 |

## Associated conditions {#conditions}

[nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/), [renal-hepatic-pancreatic dysplasia 1](https://sugi.bio/atlas/disease/renal-hepatic-pancreatic-dysplasia-1/), [NPHP3-related Meckel-like syndrome](https://sugi.bio/atlas/disease/nphp3-related-meckel-like-syndrome/), [nephronophthisis 3](https://sugi.bio/atlas/disease/nephronophthisis-3/).

**Reported phenotype names (ClinVar):** Nephronophthisis, not provided, NPHP3-related Meckel-like syndrome, Nephronophthisis 3, Renal-hepatic-pancreatic dysplasia 1, not specified, Juvenile Nephronophthisis, Adolescent nephronophthisis, Meckel syndrome type 7, GOLDSTON SYNDROME.

### 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 843396). 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.*