# NM_022341.2(PDF):c.19G>C (p.Ala7Pro)

https://sugi.bio/variant/pdf-p-ala7pro

## Summary

**PDF p.Ala7Pro (c.19G>C)** is classified **Uncertain significance** in PDF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: likely benign (0.0784); Very rare (popmax 0.00251%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00251%, amr)

## For patients & families {#patients}

This is a change in the PDF gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PDF](https://sugi.bio/atlas/gene/PDF/) |
| Protein change (HGVS p.) | p.Ala7Pro |
| Coding change (HGVS c.) | c.19G>C |
| MANE Select transcript | [NM_032382](https://www.ncbi.nlm.nih.gov/nuccore/NM_032382) (variant reported on NM_022341) |
| Variant type | single nucleotide variant |
| Location | chr16:69330552-69330552 (GRCh38) |
| ClinVar | [VCV4566357](https://www.ncbi.nlm.nih.gov/clinvar/variation/4566357/) |

**All HGVS expressions:** `NC_000016.10:g.69330552C>G`, `NC_000016.9:g.69364455C>G`, `NG_009013.1:g.14072G>C`, `NG_009013.2:g.14012G>C`, `NG_033043.1:g.5044G>C`, `NG_134175.1:g.699C>G`, `NG_134175.2:g.699C>G`, `NG_193725.1:g.17C>G`, `NM_001379261.1:c.*26+261G>C`, `NM_001379262.1:c.1759+367G>C`, `NM_001379263.1:c.*26+261G>C`, `NM_001379264.1:c.*23+264G>C`, `NM_001379265.1:c.1583-1373G>C`, `NM_001379266.1:c.1414-1373G>C`, `NM_022341.2:c.19G>C`, `NM_032382.5:c.*26+261G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0784)
- REVEL 0.057 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.328 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -1.875, GERP -3.06 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.31**. 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 1.23** across the covering region of the MANE Select transcript (69,329,025–69,330,570), spanning 1,545 bp. Chi-square p 9e-06. 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 **0.00251%** (amr) · FAF95 3e-05% · FAF99 1.1e-05% · 1/39,790 in the highest group · 3/1,317,510 alleles overall — very rare (popmax 0.00251%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00251% | 39,790 |
| European (non-Finnish) | 0.000179% | 560,026 |

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-21.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-21 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 4566357). 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.*