# NM_033163.5(FGF8):c.386G>C (p.Arg129Pro)

https://sugi.bio/variant/fgf8-p-arg129pro

## Summary

**FGF8 p.Arg129Pro (c.386G>C)** is classified **Conflicting classifications of pathogenicity** in FGF8 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-23). AlphaMissense: likely pathogenic (0.9986); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs769756528 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the FGF8 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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 | [FGF8](https://sugi.bio/atlas/gene/FGF8/) |
| Protein change (HGVS p.) | p.Arg129Pro |
| Coding change (HGVS c.) | c.386G>C |
| MANE Select transcript | [NM_033163](https://www.ncbi.nlm.nih.gov/nuccore/NM_033163) |
| dbSNP | [rs769756528](https://www.ncbi.nlm.nih.gov/snp/rs769756528/) |
| Variant type | single nucleotide variant |
| Location | chr10:101771521-101771521 (GRCh38) |
| ClinVar | [VCV2874053](https://www.ncbi.nlm.nih.gov/clinvar/variation/2874053/) |

**All HGVS expressions:** `NC_000010.10:g.103531278C>G`, `NC_000010.11:g.101771521C>G`, `NG_007151.1:g.9550G>C`, `NM_001206389.2:c.74G>C`, `NM_006119.6:c.299G>C`, `NM_033163.3:c.386G>C`, `NM_033163.5:c.386G>C`, `NM_033164.4:c.353G>C`, `NM_033165.5:c.266G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9986)
- REVEL 0.693 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.416 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.603, GERP 0.941, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R118P** vs ClinVar **R129P**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in FGF8 (of 1,368 modeled).
- CADD: **PHRED 32.0**. 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 0.81** across the covering region of the MANE Select transcript (101,770,609–101,775,900), spanning 5,291 bp. Chi-square p 0.0067. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for FGF8 (234 scored positions, the nearest 34 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- 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}

**FGF8** population constraint: LOEUF 0.765, pLI 0.060739, missense-Z 1.0173. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **congenital heart disease** — Moderate (AD)

## Protein context {#protein}

Residue **118** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 81.34, 63% of residues very-high.

**1 experimental structure(s)** (PDB): [2FDB](https://www.rcsb.org/structure/2FDB).

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

*Describes the biological roles of FGF8 (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:** FGF8's established molecular role includes type 1 fibroblast growth factor receptor binding. In Reactome, FGF8 is annotated in disease pathway(s) including **Activated point mutants of FGFR2**, **Constitutive Signaling by Aberrant PI3K in Cancer**.

**Disease mechanism (Reactome):** FGF8 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}

FGF8 participates in **39 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 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 |
| [FGFR3b ligand binding and activation](https://reactome.org/content/detail/R-HSA-190371) | 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 |
| [Formation of the posterior neural plate](https://reactome.org/content/detail/R-HSA-9832991) | electronic |
| [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 |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | 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}

**Molecular function:** type 1 fibroblast growth factor receptor binding, type 2 fibroblast growth factor receptor binding, growth factor activity.

**Biological process:** metanephros development, mesonephros development, positive regulation of cell population proliferation, gonad development, fibroblast growth factor receptor signaling pathway, odontogenesis.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-04-23.

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

**Submission history:** 2 submissions (2023–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-03-01 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, none provided.

## Same-residue context {#hotspot}

Residue **129** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [FGF8 p.Arg129Ter](/variant/fgf8-p-arg129ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FGF8 variant pages (same residue, condition, or type): [FGF8 p.Arg129Gln](/variant/fgf8-p-arg129gln), [FGF8 p.Arg129Ter](/variant/fgf8-p-arg129ter), [FGF8 p.Ala147Thr](/variant/fgf8-p-ala147thr), [FGF8 p.Arg195Trp](/variant/fgf8-p-arg195trp), [FGF8 p.Arg233Cys](/variant/fgf8-p-arg233cys), [FGF8 p.Thr72=](/variant/fgf8-p-thr72), [FGF8 p.Ala7Gly](/variant/fgf8-p-ala7gly), [FGF8 p.Arg189Cys](/variant/fgf8-p-arg189cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2874053). 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.*