# NM_002004.4(FDPS):c.189C>T (p.Ser63=)

https://sugi.bio/variant/fdps-p-ser63

## Summary

**FDPS p.Ser63= (c.189C>T)** is classified **Benign** in FDPS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-03-23). Rare (popmax 0.141%, nfe); Associated with FDPS-related disorder.

**At a glance:** Benign · review: No assertion criteria · rsID rs143038155 · 1 submitter · 1 linked condition · rare (popmax 0.141%, nfe)

## For patients & families {#patients}

This is a change in the FDPS gene that is classified as benign — not considered disease-causing, submitted by 1 submitter, and is linked to FDPS-related disorder.

*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 | [FDPS](https://sugi.bio/atlas/gene/FDPS/) |
| Protein change (HGVS p.) | p.Ser63= |
| Coding change (HGVS c.) | c.189C>T |
| MANE Select transcript | [NM_002004](https://www.ncbi.nlm.nih.gov/nuccore/NM_002004) |
| dbSNP | [rs143038155](https://www.ncbi.nlm.nih.gov/snp/rs143038155/) |
| Variant type | single nucleotide variant |
| Location | chr1:155310055-155310055 (GRCh38) |
| ClinVar | [VCV3041400](https://www.ncbi.nlm.nih.gov/clinvar/variation/3041400/) |

**All HGVS expressions:** `NC_000001.10:g.155279846C>T`, `NC_000001.11:g.155310055C>T`, `NG_045218.1:g.6308C>T`, `NM_001135821.2:c.189C>T`, `NM_001135822.2:c.-1-9C>T`, `NM_001242824.2:c.-10C>T`, `NM_001242825.2:c.-175+1090C>T`, `NM_001378424.1:c.-1-9C>T`, `NM_001378425.1:c.-10C>T`, `NM_002004.4:c.189C>T`

## 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 0.55, GERP 2.05, phastCons 0.972 — weakly conserved position
- CADD: **PHRED 16.61**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.30 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.*
- Pangolin: Δ**0.31** (gain), gain 0.31 / loss 0.16. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.141%** (nfe) · FAF95 0.135% · FAF99 0.133% · 1,664/1,180,020 in the highest group · 2,989/1,613,606 alleles overall — rare (popmax 0.141%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 4.61% | 22 |
| Finnish (not grpmax-eligible) | 1.79% | 56 |
| Remaining individuals (not grpmax-eligible) | 0.186% | 538 |
| European (non-Finnish) (grpmax) | 0.141% | 709 |
| African / African-American | 0.02% | 5,001 |
| Middle Eastern | 0.0178% | 5,604 |
| Admixed American | 0.00666% | 15,006 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**FDPS** population constraint: LOEUF 0.744, pLI 9.0341e-05, missense-Z 1.8797. *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 85.27, 77% of residues very-high.

**92 experimental structure(s)** (PDB): [1YQ7](https://www.rcsb.org/structure/1YQ7), [1YV5](https://www.rcsb.org/structure/1YV5), [1ZW5](https://www.rcsb.org/structure/1ZW5), [2F7M](https://www.rcsb.org/structure/2F7M), [2F89](https://www.rcsb.org/structure/2F89), [2F8C](https://www.rcsb.org/structure/2F8C) — incl. mutant structure 2QIS.

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

*Describes the biological roles of FDPS (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:** FDPS's established molecular role includes RNA binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of gene expression by SREBF (SREBP)](https://reactome.org/content/detail/R-HSA-2426168) | curated |
| [Lanosterol biosynthesis](https://reactome.org/content/detail/R-HSA-9969896) | curated |

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

**Molecular function:** RNA binding.

## Clinical significance {#significance}

**Benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2020-03-23.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2020-03-23 |

## Associated conditions {#conditions}

[FDPS-related disorder](https://sugi.bio/atlas/disease/fdps-related-disorder/).

**Reported phenotype names (ClinVar):** FDPS-related disorder, FDPS-related condition.

## Similar variants {#similar}

Related FDPS variant pages (same residue, condition, or type): [FDPS p.Trp26Ter](/variant/fdps-p-trp26ter), [FDPS p.Arg48Cys](/variant/fdps-p-arg48cys), [FDPS p.Ile120Thr](/variant/fdps-p-ile120thr), [FDPS p.Tyr219=](/variant/fdps-p-tyr219), [FDPS p.Val364Ala](/variant/fdps-p-val364ala), [FDPS c.684+2T>G](/variant/fdps-c-684-plus-2t-g), [FDPS p.Ala119Val](/variant/fdps-p-ala119val), [FDPS p.Arg110Gly](/variant/fdps-p-arg110gly).

### 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 3041400). 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.*