# NM_002037.5(FYN):c.1464G>A (p.Pro488=)

https://sugi.bio/variant/fyn-p-pro488

## Summary

**FYN p.Pro488= (c.1464G>A)** is classified **Likely benign** in FYN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). Ultra-rare (popmax 0.0267%, amr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0267%, amr)

## For patients & families {#patients}

This is a change in the FYN gene that is classified as likely benign — not considered disease-causing, 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 | [FYN](https://sugi.bio/atlas/gene/FYN/) |
| Protein change (HGVS p.) | p.Pro488= |
| Coding change (HGVS c.) | c.1464G>A |
| MANE Select transcript | [NM_002037](https://www.ncbi.nlm.nih.gov/nuccore/NM_002037) |
| Variant type | single nucleotide variant |
| Location | chr6:111661889-111661889 (GRCh38) |
| ClinVar | [VCV4027439](https://www.ncbi.nlm.nih.gov/clinvar/variation/4027439/) |

**All HGVS expressions:** `NC_000006.11:g.111983092C>T`, `NC_000006.12:g.111661889C>T`, `NG_109032.1:g.628C>T`, `NM_001370529.1:c.1464G>A`, `NM_002037.5:c.1464G>A`, `NM_153047.4:c.1455G>A`, `NM_153048.4:c.1299G>A`

## 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 -4.437, GERP -5.72 — fast-evolving / accelerated position
- CADD: **PHRED 7.045**. 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: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0267%** (amr) · FAF95 0.0166% · FAF99 0.0136% · 16/60,016 in the highest group · 62/1,614,060 alleles overall — ultra-rare (popmax 0.0267%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0267% | 3,751 |
| Middle Eastern | 0.0165% | 6,062 |
| African / African-American | 0.00666% | 15,005 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,254 |
| European (non-Finnish) | 0.00314% | 31,891 |
| South Asian | 0.0011% | 91,074 |

*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}

**FYN** population constraint: LOEUF 0.215, pLI 1, missense-Z 5.241. *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 **488** lies in the protein kinase domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 81.62, 59% of residues very-high.

**53 experimental structure(s)** (PDB): [10DJ](https://www.rcsb.org/structure/10DJ), [1A0N](https://www.rcsb.org/structure/1A0N), [1AOT](https://www.rcsb.org/structure/1AOT), [1AOU](https://www.rcsb.org/structure/1AOU), [1AVZ](https://www.rcsb.org/structure/1AVZ), [1AZG](https://www.rcsb.org/structure/1AZG) — incl. mutant structure 1EFN.

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

*Describes the biological roles of FYN (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:** FYN's established molecular role includes G protein-coupled receptor binding. p.Pro488= falls in the protein kinase domain. In Reactome, FYN is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **FCGR3A-mediated IL10 synthesis**.

**Disease mechanism (Reactome):** FYN loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323), [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422).

### Pathways affected {#pathways}

FYN participates in **45 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| ⚕ [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323) | curated |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | curated |
| ⚕ [Nef and signal transduction](https://reactome.org/content/detail/R-HSA-164944) | curated |
| ⚕ [Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants](https://reactome.org/content/detail/R-HSA-9670439) | curated |
| [CD209 (DC-SIGN) signaling](https://reactome.org/content/detail/R-HSA-5621575) | curated |
| [CD28 dependent PI3K/Akt signaling](https://reactome.org/content/detail/R-HSA-389357) | curated |
| [CD28 dependent Vav1 pathway](https://reactome.org/content/detail/R-HSA-389359) | curated |
| [Cell surface interactions at the vascular wall](https://reactome.org/content/detail/R-HSA-202733) | curated |
| [Co-inhibition by CTLA4](https://reactome.org/content/detail/R-HSA-389513) | curated |
| [Co-stimulation by CD28](https://reactome.org/content/detail/R-HSA-389356) | curated |
| [Dectin-2 family](https://reactome.org/content/detail/R-HSA-5621480) | curated |
| [EPH-ephrin mediated repulsion of cells](https://reactome.org/content/detail/R-HSA-3928665) | curated |
| [FCGR activation](https://reactome.org/content/detail/R-HSA-2029481) | curated |
| [GPVI-mediated activation cascade](https://reactome.org/content/detail/R-HSA-114604) | curated |
| [PECAM1 interactions](https://reactome.org/content/detail/R-HSA-210990) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [Platelet Adhesion to exposed collagen](https://reactome.org/content/detail/R-HSA-75892) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Reelin signalling pathway](https://reactome.org/content/detail/R-HSA-8866376) | curated |
| [Regulation of KIT signaling](https://reactome.org/content/detail/R-HSA-1433559) | curated |
| [Sema3A PAK dependent Axon repulsion](https://reactome.org/content/detail/R-HSA-399954) | curated |
| [Signaling by ERBB2](https://reactome.org/content/detail/R-HSA-1227986) | curated |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | curated |
| [Activated NTRK2 signals through FYN](https://reactome.org/content/detail/R-HSA-9032500) | other |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | electronic |
| [CRMPs in Sema3A signaling](https://reactome.org/content/detail/R-HSA-399956) | electronic |
| [DAP12 signaling](https://reactome.org/content/detail/R-HSA-2424491) | electronic |
| [DCC mediated attractive signaling](https://reactome.org/content/detail/R-HSA-418885) | other |
| [Degradation of CDH1](https://reactome.org/content/detail/R-HSA-9766229) | other |
| [EPH-Ephrin signaling](https://reactome.org/content/detail/R-HSA-2682334) | electronic |
| [EPHA-mediated growth cone collapse](https://reactome.org/content/detail/R-HSA-3928663) | electronic |
| [EPHB-mediated forward signaling](https://reactome.org/content/detail/R-HSA-3928662) | electronic |
| [Ephrin signaling](https://reactome.org/content/detail/R-HSA-3928664) | electronic |
| [FLT3 signaling through SRC family kinases](https://reactome.org/content/detail/R-HSA-9706374) | electronic |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | electronic |
| [NCAM signaling for neurite out-growth](https://reactome.org/content/detail/R-HSA-375165) | electronic |
| [NTRK2 activates RAC1](https://reactome.org/content/detail/R-HSA-9032759) | other |
| [Nephrin family interactions](https://reactome.org/content/detail/R-HSA-373753) | electronic |
| [Regulation of signaling by CBL](https://reactome.org/content/detail/R-HSA-912631) | electronic |
| [Role of LAT2/NTAL/LAB on calcium mobilization](https://reactome.org/content/detail/R-HSA-2730905) | electronic |
| [SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion](https://reactome.org/content/detail/R-HSA-399955) | electronic |
| [Signaling by CSF1 (M-CSF) in myeloid cells](https://reactome.org/content/detail/R-HSA-9680350) | electronic |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | electronic |

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

**Molecular function:** G protein-coupled receptor binding, protein tyrosine kinase activity, non-membrane spanning protein tyrosine kinase activity, phospholipase activator activity, enzyme binding, identical protein binding.

**Biological process:** heart process, G protein-coupled glutamate receptor signaling pathway, natural killer cell activation, intracellular signal transduction, T cell receptor signaling pathway, negative regulation of T cell receptor signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-24.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-24 |

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

## Similar variants {#similar}

Related FYN variant pages (same residue, condition, or type): [FYN p.Asp506Glu](/variant/fyn-p-asp506glu), [FYN c.344+1G>A](/variant/fyn-c-344-plus-1g-a), [FYN p.Ala55Thr](/variant/fyn-p-ala55thr), [FYN p.Arg123Cys](/variant/fyn-p-arg123cys), [FYN p.Arg161Ter](/variant/fyn-p-arg161ter), [FYN p.Arg29Cys](/variant/fyn-p-arg29cys), [FYN p.Asp8Glu](/variant/fyn-p-asp8glu), [FYN p.Asp92Asn](/variant/fyn-p-asp92asn).

### 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 4027439). 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.*