# NM_020638.3(FGF23):c.385T>C (p.Ser129Pro)

https://sugi.bio/variant/fgf23-p-ser129pro

## Summary

**FGF23 p.Ser129Pro (c.385T>C)** is classified **Pathogenic/Likely pathogenic** in FGF23 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-13). AlphaMissense: likely pathogenic (0.9571); Absent from gnomAD v4.1; Associated with tumoral calcinosis, hyperphosphatemic, familial, 2.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1555096583 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the FGF23 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to tumoral calcinosis, hyperphosphatemic, familial, 2.

*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) | Childhood |
| Diagnostic panels | FGF23 is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Familial tumoral calcinosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Subcutaneous nodule — Very frequent (99-80%)
- Bone pain — Very frequent (99-80%)
- Periarticular subcutaneous nodules — Very frequent (99-80%)
- Calcification of muscles — Very frequent (99-80%)
- Skin rash — Frequent (79-30%)
- Erythema — Frequent (79-30%)
- Hyperostosis — Frequent (79-30%)
- Nephrocalcinosis — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016281/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FGF23](https://sugi.bio/atlas/gene/FGF23/) |
| Protein change (HGVS p.) | p.Ser129Pro |
| Coding change (HGVS c.) | c.385T>C |
| MANE Select transcript | [NM_020638](https://www.ncbi.nlm.nih.gov/nuccore/NM_020638) |
| dbSNP | [rs1555096583](https://www.ncbi.nlm.nih.gov/snp/rs1555096583/) |
| Variant type | single nucleotide variant |
| Location | chr12:4370714-4370714 (GRCh38) |
| ClinVar | [VCV444061](https://www.ncbi.nlm.nih.gov/clinvar/variation/444061/) |

**All HGVS expressions:** `NC_000012.11:g.4479880A>G`, `NC_000012.12:g.4370714A>G`, `NG_007087.1:g.14015T>C`, `NM_020638.3:c.385T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9571) — concordant with the pathogenic call
- REVEL 0.701 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -10.124 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 8.985, GERP 0.744, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in FGF23 (of 1,482 modeled).
- CADD: **PHRED 23.0**. 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 0.94** across the covering region of the MANE Select transcript (4,370,346–4,372,614), spanning 2,268 bp. Chi-square p 0.37. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **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}

**FGF23** population constraint: LOEUF 1.608, pLI 0.0087695, missense-Z 0.82946. *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 **129** lies in a UniProt-annotated variant site (in hftc2; full-length and n-terminal fragments are barely detectable, whereas a c-terminal fragment with the same molecular weight as that from wild-type can be detected).

AlphaFold model confidence (whole protein): pLDDT 77.94, 47% of residues very-high.

**6 experimental structure(s)** (PDB): [2P39](https://www.rcsb.org/structure/2P39), [5W21](https://www.rcsb.org/structure/5W21), [6S22](https://www.rcsb.org/structure/6S22), [7YSH](https://www.rcsb.org/structure/7YSH), [7YSU](https://www.rcsb.org/structure/7YSU), [7YSW](https://www.rcsb.org/structure/7YSW).

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

*Describes the biological roles of FGF23 (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:** FGF23 participates in disease-associated pathways. In Reactome, FGF23 is annotated in disease pathway(s) including **Activated point mutants of FGFR2**, **Constitutive Signaling by Aberrant PI3K in Cancer**.

**Disease mechanism (Reactome):** FGF23 loss or alteration is curated in [Activated point mutants of FGFR2](https://reactome.org/content/detail/R-HSA-2033519), [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302).

### Pathways affected {#pathways}

FGF23 participates in **40 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Activated point mutants of FGFR2](https://reactome.org/content/detail/R-HSA-2033519) | other |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | other |
| ⚕ [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302) | other |
| ⚕ [Signaling by FGFR2 in disease](https://reactome.org/content/detail/R-HSA-5655253) | other |
| ⚕ [Signaling by FGFR3 in disease](https://reactome.org/content/detail/R-HSA-5655332) | other |
| ⚕ [Signaling by activated point mutants of FGFR1](https://reactome.org/content/detail/R-HSA-1839122) | other |
| ⚕ [Signaling by activated point mutants of FGFR3](https://reactome.org/content/detail/R-HSA-1839130) | other |
| [Downstream signaling of activated FGFR1](https://reactome.org/content/detail/R-HSA-5654687) | other |
| [FGFR1c and Klotho ligand binding and activation](https://reactome.org/content/detail/R-HSA-190374) | other |
| [FGFR1c ligand binding and activation](https://reactome.org/content/detail/R-HSA-190373) | other |
| [FGFR2c ligand binding and activation](https://reactome.org/content/detail/R-HSA-190375) | other |
| [FGFR3c ligand binding and activation](https://reactome.org/content/detail/R-HSA-190372) | other |
| [FGFR4 ligand binding and activation](https://reactome.org/content/detail/R-HSA-190322) | other |
| [FGFRL1 modulation of FGFR1 signaling](https://reactome.org/content/detail/R-HSA-5658623) | other |
| [FRS-mediated FGFR1 signaling](https://reactome.org/content/detail/R-HSA-5654693) | other |
| [FRS-mediated FGFR2 signaling](https://reactome.org/content/detail/R-HSA-5654700) | other |
| [FRS-mediated FGFR3 signaling](https://reactome.org/content/detail/R-HSA-5654706) | other |
| [FRS-mediated FGFR4 signaling](https://reactome.org/content/detail/R-HSA-5654712) | other |
| [Negative regulation of FGFR1 signaling](https://reactome.org/content/detail/R-HSA-5654726) | other |
| [Negative regulation of FGFR2 signaling](https://reactome.org/content/detail/R-HSA-5654727) | other |
| [Negative regulation of FGFR3 signaling](https://reactome.org/content/detail/R-HSA-5654732) | other |
| [Negative regulation of FGFR4 signaling](https://reactome.org/content/detail/R-HSA-5654733) | other |
| [PI-3K cascade:FGFR1](https://reactome.org/content/detail/R-HSA-5654689) | other |
| [PI-3K cascade:FGFR2](https://reactome.org/content/detail/R-HSA-5654695) | other |
| [PI-3K cascade:FGFR3](https://reactome.org/content/detail/R-HSA-5654710) | other |
| [PI-3K cascade:FGFR4](https://reactome.org/content/detail/R-HSA-5654720) | other |
| [PI3K Cascade](https://reactome.org/content/detail/R-HSA-109704) | other |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | other |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | other |
| [Phospholipase C-mediated cascade: FGFR1](https://reactome.org/content/detail/R-HSA-5654219) | other |
| [Phospholipase C-mediated cascade; FGFR2](https://reactome.org/content/detail/R-HSA-5654221) | other |
| [Phospholipase C-mediated cascade; FGFR3](https://reactome.org/content/detail/R-HSA-5654227) | other |
| [Phospholipase C-mediated cascade; FGFR4](https://reactome.org/content/detail/R-HSA-5654228) | other |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | other |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | other |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | other |
| [SHC-mediated cascade:FGFR1](https://reactome.org/content/detail/R-HSA-5654688) | other |
| [SHC-mediated cascade:FGFR2](https://reactome.org/content/detail/R-HSA-5654699) | other |
| [SHC-mediated cascade:FGFR3](https://reactome.org/content/detail/R-HSA-5654704) | other |
| [SHC-mediated cascade:FGFR4](https://reactome.org/content/detail/R-HSA-5654719) | other |

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

**Biological process:** regulation of phosphate transport, negative regulation of bone mineralization, vitamin D catabolic process, negative regulation of osteoblast differentiation, phosphate ion homeostasis.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-12-13.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2017–2021); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics Munich, TUM University Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2017-09-20 |
| Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-12-13 |

## Associated conditions {#conditions}

[tumoral calcinosis, hyperphosphatemic, familial, 2](https://sugi.bio/atlas/disease/tumoral-calcinosis-hyperphosphatemic-familial-2/), [tumoral calcinosis, hyperphosphatemic, familial, 1](https://sugi.bio/atlas/disease/tumoral-calcinosis-hyperphosphatemic-familial-1/).

**Reported phenotype names (ClinVar):** Tumoral calcinosis, hyperphosphatemic, familial, 2, Tumoral calcinosis, hyperphosphatemic, familial, 1, CALCINOSIS, TUMORAL, WITH HYPERPHOSPHATEMIA, LIPOCALCINOGRANULOMATOSIS, MORBUS TEUTSCHLAENDER, TEUTSCHLAENDER DISEASE, FAMILIAL, TUMORAL CALCINOSIS, PRIMARY HYPERPHOSPHATEMIC, CORTICAL HYPEROSTOSIS WITH HYPERPHOSPHATEMIA, HYPEROSTOSIS WITH HYPERPHOSPHATEMIA, HYPEROSTOSIS-HYPERPHOSPHATEMIA SYNDROME.

## Same-residue context {#hotspot}

Residue **129** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [FGF23 p.Ser129Phe](/variant/fgf23-p-ser129phe). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FGF23 variant pages (same residue, condition, or type): [FGF23 p.Ser129Phe](/variant/fgf23-p-ser129phe), [FGF23 p.Arg179Gln](/variant/fgf23-p-arg179gln), [FGF23 p.Gly123Trp](/variant/fgf23-p-gly123trp), [FGF23 p.Ala213Thr](/variant/fgf23-p-ala213thr), [FGF23 p.Ala236Pro](/variant/fgf23-p-ala236pro), [FGF23 p.Ala45Thr](/variant/fgf23-p-ala45thr), [FGF23 p.Arg187Trp](/variant/fgf23-p-arg187trp), [FGF23 p.Arg5Cys](/variant/fgf23-p-arg5cys).

### 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 2026-10-14); 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 444061). 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.*