# NM_138694.4(PKHD1):c.447A>G (p.Pro149=)

https://sugi.bio/variant/pkhd1-p-pro149

## Summary

**PKHD1 p.Pro149= (c.447A>G)** is classified **Uncertain significance** in PKHD1 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-03-04). Very rare (popmax 8.53e-05%, nfe); Associated with autosomal recessive polycystic kidney disease.

**At a glance:** Uncertain significance · review: Single submitter · 2 submitters · 1 linked condition · very rare (popmax 8.53e-05%, nfe)

## For patients & families {#patients}

This is a change in the PKHD1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to autosomal recessive polycystic kidney disease.

*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) | All ages |
| Prevalence | 1-9 / 100 000 (Germany) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PKHD1 is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Autosomal recessive polycystic kidney disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Enlarged kidney — Very frequent (99-80%)
- Polycystic kidney dysplasia — Very frequent (99-80%)
- Hypertension — Very frequent (99-80%)
- Hepatic fibrosis — Very frequent (99-80%)
- Periportal fibrosis — Very frequent (99-80%)
- Renal insufficiency — Frequent (79-30%)
- Cholestasis — Frequent (79-30%)
- Portal hypertension — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008378/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PKHD1](https://sugi.bio/atlas/gene/PKHD1/) |
| Protein change (HGVS p.) | p.Pro149= |
| Coding change (HGVS c.) | c.447A>G |
| MANE Select transcript | [NM_138694](https://www.ncbi.nlm.nih.gov/nuccore/NM_138694) |
| Variant type | single nucleotide variant |
| Location | chr6:52076277-52076277 (GRCh38) |
| ClinVar | [VCV4060100](https://www.ncbi.nlm.nih.gov/clinvar/variation/4060100/) |

**All HGVS expressions:** `NC_000006.11:g.51941075T>C`, `NC_000006.12:g.52076277T>C`, `NG_008753.1:g.16349A>G`, `NM_138694.4:c.447A>G`, `NM_170724.3:c.447A>G`

## 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 5.048, GERP 0.802, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 17.76**. 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 **8.53e-05%** (nfe) · 1/1,172,656 in the highest group · 1/1,605,990 alleles overall — very rare (popmax 8.53e-05%, nfe).

*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}

**PKHD1** population constraint: LOEUF 0.783, pLI 2.8316e-48, missense-Z 1.7677. *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):

- **autosomal recessive polycystic kidney disease** — Definitive (AR)

## Protein context {#protein}

Residue **149** lies in the ipt/tig 2 domain.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-03-04.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2025–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2025-03-20 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-03-04 |

## Associated conditions {#conditions}

[autosomal recessive polycystic kidney disease](https://sugi.bio/atlas/disease/autosomal-recessive-polycystic-kidney-disease/).

**Reported phenotype names (ClinVar):** Autosomal recessive polycystic kidney disease, not specified, AllHighlyPenetrant, AR polycystic kidney disease.

## Same-residue context {#hotspot}

Residue **149** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PKHD1 p.Pro149fs](/variant/pkhd1-p-pro149fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PKHD1 variant pages (same residue, condition, or type): [PKHD1 p.Pro149Leu](/variant/pkhd1-p-pro149leu), [PKHD1 p.Pro149Ser](/variant/pkhd1-p-pro149ser), [PKHD1 c.11174+2T>C](/variant/pkhd1-c-11174-plus-2t-c), [PKHD1 c.11310+1G>C](/variant/pkhd1-c-11310-plus-1g-c), [PKHD1 c.11398+2T>C](/variant/pkhd1-c-11398-plus-2t-c), [PKHD1 c.11507-1G>A](/variant/pkhd1-c-11507-minus-1g-a), [PKHD1 c.11665+1G>A](/variant/pkhd1-c-11665-plus-1g-a), [PKHD1 c.1233+1G>A](/variant/pkhd1-c-1233-plus-1g-a).

### 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 4060100). 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.*