# NM_001389683.1(GOLGA3):c.2420C>T (p.Ser807Leu)

https://sugi.bio/variant/golga3-p-ser807leu

## Summary

**GOLGA3 p.Ser807Leu (c.2420C>T)** is classified **Uncertain significance** in GOLGA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely benign (0.1018); Ultra-rare (popmax 0.0433%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0433%, amr)

## For patients & families {#patients}

This is a change in the GOLGA3 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 | [GOLGA3](https://sugi.bio/atlas/gene/GOLGA3/) |
| Protein change (HGVS p.) | p.Ser807Leu |
| Coding change (HGVS c.) | c.2420C>T |
| MANE Select transcript | [NM_001389683](https://www.ncbi.nlm.nih.gov/nuccore/NM_001389683) |
| Variant type | single nucleotide variant |
| Location | chr12:132795901-132795901 (GRCh38) |
| ClinVar | [VCV4264803](https://www.ncbi.nlm.nih.gov/clinvar/variation/4264803/) |

**All HGVS expressions:** `NC_000012.11:g.133372487G>A`, `NC_000012.12:g.132795901G>A`, `NG_029887.1:g.37940C>T`, `NM_001172557.2:c.2420C>T`, `NM_001389683.1:c.2420C>T`, `NM_001389684.1:c.2420C>T`, `NM_001389685.1:c.2420C>T`, `NM_001389686.1:c.2300C>T`, `NM_001389687.1:c.2300C>T`, `NM_001389688.1:c.2300C>T`, `NM_001389689.1:c.2147C>T`, `NM_005895.4:c.2420C>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** (0.1018)
- REVEL 0.089 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.041 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.653, GERP 0.12, phastCons 0.003 — weakly conserved position
- CADD: **PHRED 20.2**. 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 0.98** across the covering region of the MANE Select transcript (132,773,108–132,822,128), spanning 49,020 bp. Chi-square p 0.48. 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>T, Δ0.39 donor 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 **0.0433%** (amr) · FAF95 0.0303% · FAF99 0.026% · 26/60,002 in the highest group · 44/1,613,948 alleles overall — ultra-rare (popmax 0.0433%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0433% | 2,308 |
| Middle Eastern | 0.0164% | 6,084 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,239 |
| East Asian | 0.00223% | 44,904 |
| African / African-American | 0.00133% | 74,916 |
| South Asian | 0.0011% | 91,086 |
| European (non-Finnish) | 0.00102% | 98,332 |

*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}

**GOLGA3** population constraint: LOEUF 0.568, pLI 1.6692e-05, missense-Z 0.29176. *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 **807** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 68.76, 7% of residues very-high.

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

*Describes the biological roles of GOLGA3 (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:** GOLGA3's established molecular role includes cadherin binding. p.Ser807Leu falls in the disordered region.


### Pathways affected {#pathways}

GOLGA3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RND2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9696270) | curated |

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

**Molecular function:** cadherin binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-09.

**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 | 2025-09-09 |

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

## Similar variants {#similar}

Related GOLGA3 variant pages (same residue, condition, or type): [GOLGA3 p.Ala563Val](/variant/golga3-p-ala563val), [GOLGA3 c.2812-1G>A](/variant/golga3-c-2812-minus-1g-a), [GOLGA3 p.Ala1015Val](/variant/golga3-p-ala1015val), [GOLGA3 p.Ala1019Pro](/variant/golga3-p-ala1019pro), [GOLGA3 p.Ala1019Thr](/variant/golga3-p-ala1019thr), [GOLGA3 p.Ala1022Thr](/variant/golga3-p-ala1022thr), [GOLGA3 p.Ala1029Val](/variant/golga3-p-ala1029val), [GOLGA3 p.Ala1070Val](/variant/golga3-p-ala1070val).

### 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 4264803). 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.*