# NM_003376.6(VEGFA):c.403G>C (p.Ala135Pro)

https://sugi.bio/variant/vegfa-p-ala135pro

## Summary

**VEGFA p.Ala135Pro (c.403G>C)** is classified **Uncertain significance** in VEGFA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-04). Ultra-rare (popmax 0.0236%, mid); Associated with prostate cancer, hereditary, 1.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0236%, mid)

## For patients & families {#patients}

This is a change in the VEGFA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to prostate cancer, hereditary, 1.

*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) | Not applicable |
| Age of onset (of this condition) | Adult |
| Prevalence | 1-9 / 100 000 (United States) |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015334/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [VEGFA](https://sugi.bio/atlas/gene/VEGFA/) |
| Protein change (HGVS p.) | p.Ala135Pro |
| Coding change (HGVS c.) | c.403G>C |
| MANE Select transcript | [NM_003376](https://www.ncbi.nlm.nih.gov/nuccore/NM_003376) |
| Variant type | single nucleotide variant |
| Location | chr6:43771109-43771109 (GRCh38) |
| ClinVar | [VCV3363179](https://www.ncbi.nlm.nih.gov/clinvar/variation/3363179/) |

**All HGVS expressions:** `NC_000006.11:g.43738846G>C`, `NC_000006.12:g.43771109G>C`, `NG_008732.1:g.5894G>C`, `NG_028283.4:g.259022G>C`, `NG_108304.1:g.574G>C`, `NG_108304.2:g.574G>C`, `NM_001025366.3:c.403G>C`, `NM_001025367.3:c.403G>C`, `NM_001025368.3:c.403G>C`, `NM_001025369.3:c.403G>C`, `NM_001025370.3:c.403G>C`, `NM_001033756.3:c.403G>C`, `NM_001171622.2:c.403G>C`, `NM_001171623.2:c.-138G>C`, `NM_001171624.2:c.-138G>C`, `NM_001171625.2:c.-138G>C`, `NM_001171626.2:c.-138G>C`, `NM_001171627.2:c.-138G>C`, `NM_001171628.2:c.-138G>C`, `NM_001171629.2:c.-138G>C`, `NM_001171630.2:c.-138G>C`, `NM_001204384.2:c.-138G>C`, `NM_001204385.2:c.403G>C`, `NM_001317010.2:c.-138G>C`, `NM_003376.6:c.403G>C`

## 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 7.995, GERP 1.48, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 25.2**. 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 1.06** across the covering region of the MANE Select transcript (43,770,707–43,777,471), spanning 6,764 bp. Chi-square p 0.31. 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 (gnomAD v4.1): grpmax **0.0236%** (mid) · 1/4,246 in the highest group · 2/1,464,408 alleles overall — ultra-rare (popmax 0.0236%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0236% | 4,246 |
| European (non-Finnish) | 8.98e-05% | 1,113,462 |

*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}

**VEGFA** population constraint: LOEUF 0.61, pLI 0.19093, missense-Z 0.20402; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *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** — Limited (AD)

## Protein context {#protein}

Residue **135** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 65.32, 29% of residues very-high.

**57 experimental structure(s)** (PDB): [1BJ1](https://www.rcsb.org/structure/1BJ1), [1CZ8](https://www.rcsb.org/structure/1CZ8), [1FLT](https://www.rcsb.org/structure/1FLT), [1KAT](https://www.rcsb.org/structure/1KAT), [1KMX](https://www.rcsb.org/structure/1KMX), [1MJV](https://www.rcsb.org/structure/1MJV) — incl. mutant structure 1MJV.

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

*Describes the biological roles of VEGFA (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:** VEGFA's established molecular role includes fibronectin binding. p.Ala135Pro falls in the disordered region. In Reactome, VEGFA is annotated in disease pathway(s) including **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** VEGFA loss or alteration is curated in [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191).

### Pathways affected {#pathways}

VEGFA participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | other |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Regulation of gene expression by Hypoxia-inducible Factor](https://reactome.org/content/detail/R-HSA-1234158) | curated |
| [Signaling by VEGF](https://reactome.org/content/detail/R-HSA-194138) | curated |
| [TFAP2 (AP-2) family regulates transcription of growth factors and their receptors](https://reactome.org/content/detail/R-HSA-8866910) | curated |
| [VEGF binds to VEGFR leading to receptor dimerization](https://reactome.org/content/detail/R-HSA-195399) | curated |
| [VEGF ligand-receptor interactions](https://reactome.org/content/detail/R-HSA-194313) | curated |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | other |
| [VEGFR2 mediated cell proliferation](https://reactome.org/content/detail/R-HSA-5218921) | other |

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

**Molecular function:** fibronectin binding, cytokine activity, platelet-derived growth factor receptor binding, vascular endothelial growth factor receptor binding, growth factor activity, heparin binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, angiogenesis, branching involved in blood vessel morphogenesis, response to hypoxia, positive regulation of protein phosphorylation, positive regulation of endothelial cell proliferation.

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-06-04.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Virology, Oncology, Biosciences and Environment, Faculty of Sciences and Techniques, Mohammedia- University Hassan II of Casablanca | Uncertain significance | no assertion criteria provided | clinical testing | 2024-06-04 |

## Associated conditions {#conditions}

[prostate cancer, hereditary, 1](https://sugi.bio/atlas/disease/prostate-cancer-hereditary-1/).

**Reported phenotype names (ClinVar):** Prostate cancer, hereditary, 1.

## Similar variants {#similar}

Related VEGFA variant pages (same residue, condition, or type): [VEGFA p.Ala169Glu](/variant/vegfa-p-ala169glu), [VEGFA p.Pro116Ala](/variant/vegfa-p-pro116ala), [VEGFA p.Ala123fs](/variant/vegfa-p-ala123fs), [VEGFA p.Gln108fs](/variant/vegfa-p-gln108fs), [VEGFA p.Gly117fs](/variant/vegfa-p-gly117fs), [VEGFA p.Leu111fs](/variant/vegfa-p-leu111fs), [VEGFA p.Pro107fs](/variant/vegfa-p-pro107fs), [VEGFA p.Ser164fs](/variant/vegfa-p-ser164fs).

### 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 3363179). 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.*