# NM_004957.6(FPGS):c.1204C>T (p.Pro402Ser)

https://sugi.bio/variant/fpgs-p-pro402ser

## Summary

**FPGS p.Pro402Ser (c.1204C>T)** is classified **Uncertain significance** in FPGS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-25). AlphaMissense: likely benign (0.0759); Very rare (popmax 0.00285%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00285%, sas)

## For patients & families {#patients}

This is a change in the FPGS 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 | [FPGS](https://sugi.bio/atlas/gene/FPGS/) |
| Protein change (HGVS p.) | p.Pro402Ser |
| Coding change (HGVS c.) | c.1204C>T |
| MANE Select transcript | [NM_004957](https://www.ncbi.nlm.nih.gov/nuccore/NM_004957) |
| Variant type | single nucleotide variant |
| Location | chr9:127809827-127809827 (GRCh38) |
| ClinVar | [VCV3516950](https://www.ncbi.nlm.nih.gov/clinvar/variation/3516950/) |

**All HGVS expressions:** `NC_000009.11:g.130572106C>T`, `NC_000009.12:g.127809827C>T`, `NG_023245.1:g.11953C>T`, `NG_117584.1:g.453C>T`, `NM_001018078.2:c.1054C>T`, `NM_001288803.1:c.1126C>T`, `NM_004957.6:c.1204C>T`, `NR_110170.1:n.1252C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0759)
- REVEL 0.024 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.069 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.43) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.788, GERP 1.31 — weakly conserved position
- CADD: **PHRED 16.01**. 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 0.97** across the covering region of the MANE Select transcript (127,808,694–127,813,601), spanning 4,907 bp. Chi-square p 0.5. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.43**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.43**.
- Population frequency (gnomAD v4.1): grpmax **0.00285%** (sas) · FAF95 0.000472% · FAF99 0.000177% · 2/70,294 in the highest group · 3/1,292,126 alleles overall — very rare (popmax 0.00285%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00285% | 35,147 |
| Remaining individuals (not grpmax-eligible) | 0.0018% | 55,476 |

*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}

**FPGS** population constraint: LOEUF 1.174, pLI 2.2705e-17, missense-Z 0.68257. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.05, 63% of residues very-high.

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

*Describes the biological roles of FPGS (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.*

**How this variant is thought to act:** FPGS's established molecular role includes tetrahydrofolylpolyglutamate synthase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Metabolism of folate and pterines](https://reactome.org/content/detail/R-HSA-196757) | other |

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

**Molecular function:** tetrahydrofolylpolyglutamate synthase activity.

**Biological process:** glutamate metabolic process, folic acid-containing compound metabolic process, cell population proliferation, tetrahydrofolylpolyglutamate biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-25.

**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 | 2024-10-25 |

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

## Similar variants {#similar}

Related FPGS variant pages (same residue, condition, or type): [FPGS p.Pro402Ala](/variant/fpgs-p-pro402ala), [FPGS p.Ile22Val](/variant/fpgs-p-ile22val), [FPGS p.Ala10Ser](/variant/fpgs-p-ala10ser), [FPGS p.Ala15Gly](/variant/fpgs-p-ala15gly), [FPGS p.Ala19Gly](/variant/fpgs-p-ala19gly), [FPGS p.Ala307Ser](/variant/fpgs-p-ala307ser), [FPGS p.Ala395Thr](/variant/fpgs-p-ala395thr), [FPGS p.Ala423Gly](/variant/fpgs-p-ala423gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 3516950). 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.*