# NM_014030.4(GIT1):c.1708T>G (p.Ser570Ala)

https://sugi.bio/variant/git1-p-ser570ala

## Summary

**GIT1 p.Ser570Ala (c.1708T>G)** is classified **Uncertain significance** in GIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-04). AlphaMissense: likely benign (0.0625); Very rare (popmax 0.00168%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs758929748 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00168%, amr)

## For patients & families {#patients}

This is a change in the GIT1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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 | [GIT1](https://sugi.bio/atlas/gene/GIT1/) |
| Protein change (HGVS p.) | p.Ser570Ala |
| Coding change (HGVS c.) | c.1708T>G |
| MANE Select transcript | [NM_014030](https://www.ncbi.nlm.nih.gov/nuccore/NM_014030) |
| dbSNP | [rs758929748](https://www.ncbi.nlm.nih.gov/snp/rs758929748/) |
| Variant type | single nucleotide variant |
| Location | chr17:29575856-29575856 (GRCh38) |
| ClinVar | [VCV3099909](https://www.ncbi.nlm.nih.gov/clinvar/variation/3099909/) |

**All HGVS expressions:** `NC_000017.10:g.27902874A>C`, `NC_000017.11:g.29575856A>C`, `NM_001085454.2:c.1735T>G`, `NM_014030.4:c.1708T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0625)
- REVEL 0.166 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.109 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.27) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 6.151, GERP -0.607, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.3**. 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 0.89** across the covering region of the MANE Select transcript (29,575,701–29,577,220), spanning 1,519 bp. Chi-square p 0.045. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.27**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.01**. Largest is acceptor loss, 27 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00168%** (amr) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/59,690 in the highest group · 4/1,611,952 alleles overall — very rare (popmax 0.00168%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00168% | 59,690 |
| European (non-Finnish) | 0.000254% | 393,035 |

*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}

**GIT1** population constraint: LOEUF 0.257, pLI 1, missense-Z 3.3718. *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 **570** lies in the 'interaction with nck2 and grin3a' region; the 'required for localization at synapses' region; the 'interaction with ikbkg' region.

AlphaFold model confidence (whole protein): pLDDT 74.72, 55% of residues very-high.

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

*Describes the biological roles of GIT1 (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:** GIT1's established molecular role includes gamma-tubulin binding. p.Ser570Ala falls in the interaction with nck2 and grin3a region.


### Pathways affected {#pathways}

GIT1 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOJ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013409) | curated |
| [RHOQ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013406) | curated |
| [RHOU GTPase cycle](https://reactome.org/content/detail/R-HSA-9013420) | curated |
| [RHOV GTPase cycle](https://reactome.org/content/detail/R-HSA-9013424) | curated |
| [Activation of RAC1 downstream of NMDARs](https://reactome.org/content/detail/R-HSA-9619229) | electronic |
| [Ephrin signaling](https://reactome.org/content/detail/R-HSA-3928664) | electronic |

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

**Molecular function:** gamma-tubulin binding.

**Biological process:** regulation of cytokinesis, positive regulation of microtubule nucleation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-04.

**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 | 2024-03-04 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related GIT1 variant pages (same residue, condition, or type): [GIT1 c.762-205C>T](/variant/git1-c-762-minus-205c-t), [GIT1 p.Ala130Thr](/variant/git1-p-ala130thr), [GIT1 p.Ala183Gly](/variant/git1-p-ala183gly), [GIT1 p.Ala311Val](/variant/git1-p-ala311val), [GIT1 p.Ala402Thr](/variant/git1-p-ala402thr), [GIT1 p.Ala466Val](/variant/git1-p-ala466val), [GIT1 p.Ala488Thr](/variant/git1-p-ala488thr), [GIT1 p.Ala488Val](/variant/git1-p-ala488val).

### 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 3099909). 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.*