# NM_002631.4(PGD):c.1286T>C (p.Phe429Ser)

https://sugi.bio/variant/pgd-p-phe429ser

## Summary

**PGD p.Phe429Ser (c.1286T>C)** is classified **Uncertain significance** in PGD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely pathogenic (0.9685); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PGD 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 | [PGD](https://sugi.bio/atlas/gene/PGD/) |
| Protein change (HGVS p.) | p.Phe429Ser |
| Coding change (HGVS c.) | c.1286T>C |
| MANE Select transcript | [NM_002631](https://www.ncbi.nlm.nih.gov/nuccore/NM_002631) |
| Variant type | single nucleotide variant |
| Location | chr1:10419493-10419493 (GRCh38) |
| ClinVar | [VCV4567167](https://www.ncbi.nlm.nih.gov/clinvar/variation/4567167/) |

**All HGVS expressions:** `NC_000001.10:g.10479550T>C`, `NC_000001.11:g.10419493T>C`, `NM_001304451.2:c.1220T>C`, `NM_001304452.2:c.1247T>C`, `NM_002631.4:c.1286T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9685)
- REVEL 0.83 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.985 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.76, GERP 1.85, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 29.5**. 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 0.77** across the covering region of the MANE Select transcript (10,399,118–10,419,524), spanning 20,406 bp. Chi-square p 1e-07. 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 (T>A, Δ0.24 acceptor loss), 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.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**PGD** population constraint: LOEUF 0.552, pLI 0.84096, missense-Z 2.1229. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **429** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 96.98, 96% of residues very-high.

**4 experimental structure(s)** (PDB): [2JKV](https://www.rcsb.org/structure/2JKV), [4GWG](https://www.rcsb.org/structure/4GWG), [4GWK](https://www.rcsb.org/structure/4GWK), [5UQ9](https://www.rcsb.org/structure/5UQ9).

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

*Describes the biological roles of PGD (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}

PGD participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [NFE2L2 regulates pentose phosphate pathway genes](https://reactome.org/content/detail/R-HSA-9818028) | curated |
| [Pentose phosphate pathway](https://reactome.org/content/detail/R-HSA-71336) | curated |

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

**Biological process:** pentose-phosphate shunt, oxidative branch.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-29.

**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 | 2025-10-29 |

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

## Similar variants {#similar}

Related PGD variant pages (same residue, condition, or type): [PGD c.519+2C>T](/variant/pgd-c-519-plus-2c-t), [PGD p.Ala149Gly](/variant/pgd-p-ala149gly), [PGD p.Ala258Val](/variant/pgd-p-ala258val), [PGD p.Ala336Pro](/variant/pgd-p-ala336pro), [PGD p.Ala345Gly](/variant/pgd-p-ala345gly), [PGD p.Arg407Gln](/variant/pgd-p-arg407gln), [PGD p.Asn354Ser](/variant/pgd-p-asn354ser), [PGD p.Asn354Tyr](/variant/pgd-p-asn354tyr).

### 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 4567167). 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.*