# NM_003370.4(VASP):c.203G>C (p.Arg68Pro)

https://sugi.bio/variant/vasp-p-arg68pro

## Summary

**VASP p.Arg68Pro (c.203G>C)** is classified **Uncertain significance** in VASP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.6028); Very rare (popmax 0.00177%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00177%, amr)

## For patients & families {#patients}

This is a change in the VASP 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 | [VASP](https://sugi.bio/atlas/gene/VASP/) |
| Protein change (HGVS p.) | p.Arg68Pro |
| Coding change (HGVS c.) | c.203G>C |
| MANE Select transcript | [NM_003370](https://www.ncbi.nlm.nih.gov/nuccore/NM_003370) |
| Variant type | single nucleotide variant |
| Location | chr19:45517954-45517954 (GRCh38) |
| ClinVar | [VCV4198397](https://www.ncbi.nlm.nih.gov/clinvar/variation/4198397/) |

**All HGVS expressions:** `NC_000019.10:g.45517954G>C`, `NC_000019.9:g.46021212G>C`, `NM_003370.4:c.203G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6028)
- REVEL 0.251 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -8.941 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 9.613, GERP -3.96, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.9**. 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 0.74** across the covering region of the MANE Select transcript (45,507,772–45,521,325), spanning 13,553 bp. Chi-square p 0.00082. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>A, Δ0.21 acceptor gain), 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.*
- Population frequency (gnomAD v4.1): grpmax **0.00177%** (amr) · 1/56,566 in the highest group · 3/1,525,234 alleles overall — very rare (popmax 0.00177%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00177% | 56,566 |
| Remaining individuals (not grpmax-eligible) | 0.00176% | 56,788 |
| European (non-Finnish) | 8.89e-05% | 1,125,066 |

*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}

**VASP** population constraint: LOEUF 0.746, pLI 0.00013286, missense-Z 0.096124. *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 **68** lies in the wh1 domain.

AlphaFold model confidence (whole protein): pLDDT 71.43, 38% of residues very-high.

**11 experimental structure(s)** (PDB): [1EGX](https://www.rcsb.org/structure/1EGX), [1USD](https://www.rcsb.org/structure/1USD), [1USE](https://www.rcsb.org/structure/1USE), [2PAV](https://www.rcsb.org/structure/2PAV), [2PBD](https://www.rcsb.org/structure/2PBD), [3CHW](https://www.rcsb.org/structure/3CHW).

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

*Describes the biological roles of VASP (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:** VASP's established molecular role includes profilin binding. p.Arg68Pro falls in the wh1 domain.


### Pathways affected {#pathways}

VASP participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cell-extracellular matrix interactions](https://reactome.org/content/detail/R-HSA-446353) | curated |
| [Generation of second messenger molecules](https://reactome.org/content/detail/R-HSA-202433) | electronic |
| [Signaling by ROBO receptors](https://reactome.org/content/detail/R-HSA-376176) | electronic |

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

**Molecular function:** profilin binding, cadherin binding.

**Biological process:** positive regulation of actin filament polymerization.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-29.

**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 | 2025-08-29 |

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

## Similar variants {#similar}

Related VASP variant pages (same residue, condition, or type): [VASP p.Arg68Gln](/variant/vasp-p-arg68gln), [VASP p.Arg68Trp](/variant/vasp-p-arg68trp), [VASP p.Ala104Thr](/variant/vasp-p-ala104thr), [VASP p.Ala112Val](/variant/vasp-p-ala112val), [VASP p.Arg10Gln](/variant/vasp-p-arg10gln), [VASP p.Arg22Gln](/variant/vasp-p-arg22gln), [VASP p.Arg377Gln](/variant/vasp-p-arg377gln), [VASP p.Asn45Lys](/variant/vasp-p-asn45lys).

### 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 4198397). 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.*