# NM_174931.4(GPATCH11):c.390C>G (p.Ser130Arg)

https://sugi.bio/variant/gpatch11-p-ser130arg

## Summary

**GPATCH11 p.Ser130Arg (c.390C>G)** is classified **Uncertain significance** in GPATCH11 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-04). AlphaMissense: likely benign (0.2502); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2466837402 · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GPATCH11 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 | [GPATCH11](https://sugi.bio/atlas/gene/GPATCH11/) |
| Protein change (HGVS p.) | p.Ser130Arg |
| Coding change (HGVS c.) | c.390C>G |
| MANE Select transcript | [NM_174931](https://www.ncbi.nlm.nih.gov/nuccore/NM_174931) |
| dbSNP | [rs2466837402](https://www.ncbi.nlm.nih.gov/snp/rs2466837402/) |
| Variant type | single nucleotide variant |
| Location | chr2:37091977-37091977 (GRCh38) |
| ClinVar | [VCV2269478](https://www.ncbi.nlm.nih.gov/clinvar/variation/2269478/) |

**All HGVS expressions:** `NC_000002.11:g.37319120C>G`, `NC_000002.12:g.37091977C>G`, `NM_001278505.2:c.69C>G`, `NM_001322249.4:c.348C>G`, `NM_001371856.3:c.390C>G`, `NM_001371858.3:c.390C>G`, `NM_001371859.3:c.390C>G`, `NM_001371860.3:c.387C>G`, `NM_001371861.3:c.387C>G`, `NM_001371862.3:c.390C>G`, `NM_174931.4:c.390C>G`, `NR_163986.1:n.456C>G`, `NR_163987.1:n.187C>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** (0.2502)
- REVEL 0.014 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.285 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.996, GERP -1.41, phastCons 0.998 — weakly conserved position
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **S152R** vs ClinVar **S130R**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 20.7**. 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 1.07** across the covering region of the MANE Select transcript (37,088,382–37,096,260), spanning 7,878 bp. Chi-square p 0.23. 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 **0.00**, acceptor gain **0.00**, donor gain **0.23**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.23**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**GPATCH11** population constraint: LOEUF 1.008, pLI 0.00044386, missense-Z -0.080825. *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 80.60, 42% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-04.

**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 | 2022-01-04 |

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

## Similar variants {#similar}

Related GPATCH11 variant pages (same residue, condition, or type): [GPATCH11 p.Ala146Ser](/variant/gpatch11-p-ala146ser), [GPATCH11 p.Ala36Val](/variant/gpatch11-p-ala36val), [GPATCH11 p.Ala46Val](/variant/gpatch11-p-ala46val), [GPATCH11 p.Arg152Gln](/variant/gpatch11-p-arg152gln), [GPATCH11 p.Asn75Lys](/variant/gpatch11-p-asn75lys), [GPATCH11 p.Asp10Glu](/variant/gpatch11-p-asp10glu), [GPATCH11 p.Asp177Gly](/variant/gpatch11-p-asp177gly), [GPATCH11 p.Asp208Glu](/variant/gpatch11-p-asp208glu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2269478). 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.*