# NM_005248.3(FGR):c.179C>T (p.Ala60Val)

https://sugi.bio/variant/fgr-p-ala60val

## Summary

**FGR p.Ala60Val (c.179C>T)** is classified **Uncertain significance** in FGR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-12). AlphaMissense: likely benign (0.0732); Ultra-rare (popmax 0.0267%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs761114087 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0267%, afr)

## For patients & families {#patients}

This is a change in the FGR 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 | [FGR](https://sugi.bio/atlas/gene/FGR/) |
| Protein change (HGVS p.) | p.Ala60Val |
| Coding change (HGVS c.) | c.179C>T |
| MANE Select transcript | [NM_005248](https://www.ncbi.nlm.nih.gov/nuccore/NM_005248) |
| dbSNP | [rs761114087](https://www.ncbi.nlm.nih.gov/snp/rs761114087/) |
| Variant type | single nucleotide variant |
| Location | chr1:27623738-27623738 (GRCh38) |
| ClinVar | [VCV3094866](https://www.ncbi.nlm.nih.gov/clinvar/variation/3094866/) |

**All HGVS expressions:** `NC_000001.10:g.27950249G>A`, `NC_000001.11:g.27623738G>A`, `NG_090217.1:g.327G>A`, `NM_001042729.2:c.179C>T`, `NM_001042747.2:c.179C>T`, `NM_005248.3:c.179C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0732)
- REVEL 0.116 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.822 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.325, GERP -2.29, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 17.05**. 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 (27,612,917–27,623,916), spanning 10,999 bp. Chi-square p 7.9e-12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.20**, donor gain **0.04**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.04**.
- Population frequency (gnomAD v4.1): grpmax **0.0267%** (afr) · FAF95 0.0177% · FAF99 0.0147% · 20/74,932 in the highest group · 22/1,614,110 alleles overall — ultra-rare (popmax 0.0267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0267% | 3,747 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,244 |

*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}

**FGR** population constraint: LOEUF 0.556, pLI 0.49503, missense-Z 2.6968. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.00, 65% of residues very-high.

**7 experimental structure(s)** (PDB): [10DT](https://www.rcsb.org/structure/10DT), [10FS](https://www.rcsb.org/structure/10FS), [10FV](https://www.rcsb.org/structure/10FV), [10GA](https://www.rcsb.org/structure/10GA), [7JT9](https://www.rcsb.org/structure/7JT9), [7UY0](https://www.rcsb.org/structure/7UY0) — incl. mutant structure 10FS.

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

*Describes the biological roles of FGR (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:** FGR's established molecular role includes phosphotyrosine residue binding. In Reactome, FGR is annotated in disease pathway(s) including **FCGR3A-mediated IL10 synthesis**, **FCGR3A-mediated phagocytosis**.

**Disease mechanism (Reactome):** FGR loss or alteration is curated in [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}

FGR participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [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 |
| [FCGR activation](https://reactome.org/content/detail/R-HSA-2029481) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Platelet sensitization by LDL](https://reactome.org/content/detail/R-HSA-432142) | curated |

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

**Molecular function:** phosphotyrosine residue binding, protein tyrosine kinase activity, non-membrane spanning protein tyrosine kinase activity, Fc-gamma receptor I complex binding.

**Biological process:** integrin-mediated signaling pathway, peptidyl-tyrosine phosphorylation, protein autophosphorylation, positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-12.

**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 | 2024-01-12 |

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

## Similar variants {#similar}

Related FGR variant pages (same residue, condition, or type): [FGR p.Ala60Thr](/variant/fgr-p-ala60thr), [FGR c.533-8C>G](/variant/fgr-c-533-minus-8c-g), [FGR p.Asp254=](/variant/fgr-p-asp254), [FGR p.Ser122=](/variant/fgr-p-ser122), [FGR p.Ala30Thr](/variant/fgr-p-ala30thr), [FGR p.Ala395Thr](/variant/fgr-p-ala395thr), [FGR p.Arg384Lys](/variant/fgr-p-arg384lys), [FGR p.Arg465Trp](/variant/fgr-p-arg465trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 3094866). 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.*