# NM_014030.4(GIT1):c.1254C>T (p.Asp418=)

https://sugi.bio/variant/git1-p-asp418

## Summary

**GIT1 p.Asp418= (c.1254C>T)** is classified **Likely benign** in GIT1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-03-07). Ultra-rare (popmax 0.0418%, nfe); Associated with GIT1-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs199698909 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0418%, nfe)

## For patients & families {#patients}

This is a change in the GIT1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to GIT1-related disorder.

*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.Asp418= |
| Coding change (HGVS c.) | c.1254C>T |
| MANE Select transcript | [NM_014030](https://www.ncbi.nlm.nih.gov/nuccore/NM_014030) |
| dbSNP | [rs199698909](https://www.ncbi.nlm.nih.gov/snp/rs199698909/) |
| Variant type | single nucleotide variant |
| Location | chr17:29576648-29576648 (GRCh38) |
| ClinVar | [VCV3048055](https://www.ncbi.nlm.nih.gov/clinvar/variation/3048055/) |

**All HGVS expressions:** `NC_000017.10:g.27903666G>A`, `NC_000017.11:g.29576648G>A`, `NM_001085454.2:c.1281C>T`, `NM_014030.4:c.1254C>T`

## 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 -7.949, GERP -3.79 — fast-evolving / accelerated position
- CADD: **PHRED 1.116**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.24 acceptor loss), 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 **0.0418%** (nfe) · FAF95 0.0387% · FAF99 0.0375% · 493/1,179,994 in the highest group · 560/1,613,866 alleles overall — ultra-rare (popmax 0.0418%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0864% | 1,157 |
| European (non-Finnish) (grpmax) | 0.0418% | 2,393 |
| African / African-American | 0.00667% | 14,986 |
| Finnish (not grpmax-eligible) | 0.0047% | 21,289 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,606 |
| East Asian | 0.00223% | 44,898 |
| South Asian | 0.0022% | 45,544 |
| Admixed American | 0.00167% | 60,006 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **418** lies in the 'interaction with nck2 and grin3a' region; the 'required for localization at synapses' region; the 'interaction with mapk1' 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.Asp418= 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}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-03-07.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-03-07 |

## Associated conditions {#conditions}

[GIT1-related disorder](https://sugi.bio/atlas/disease/git1-related-disorder/).

**Reported phenotype names (ClinVar):** GIT1-related disorder, GIT1-related condition.

## Similar variants {#similar}

Related GIT1 variant pages (same residue, condition, or type): [GIT1 c.2010-4G>A](/variant/git1-c-2010-minus-4g-a), [GIT1 p.Ala515=](/variant/git1-p-ala515), [GIT1 p.Arg717=](/variant/git1-p-arg717), [GIT1 p.Gln250=](/variant/git1-p-gln250), [GIT1 p.Glu221=](/variant/git1-p-glu221), [GIT1 p.Glu622=](/variant/git1-p-glu622), [GIT1 p.His50=](/variant/git1-p-his50), [GIT1 p.Leu516=](/variant/git1-p-leu516).

### 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 3048055). 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.*