# NM_022078.3(GPATCH3):c.1351C>T (p.Arg451Cys)

https://sugi.bio/variant/gpatch3-p-arg451cys

## Summary

**GPATCH3 p.Arg451Cys (c.1351C>T)** is classified **Uncertain significance** in GPATCH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.1792); Very rare (popmax 0.00223%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the GPATCH3 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 | [GPATCH3](https://sugi.bio/atlas/gene/GPATCH3/) |
| Protein change (HGVS p.) | p.Arg451Cys |
| Coding change (HGVS c.) | c.1351C>T |
| MANE Select transcript | [NM_022078](https://www.ncbi.nlm.nih.gov/nuccore/NM_022078) |
| Variant type | single nucleotide variant |
| Location | chr1:26892421-26892421 (GRCh38) |
| ClinVar | [VCV4265405](https://www.ncbi.nlm.nih.gov/clinvar/variation/4265405/) |

**All HGVS expressions:** `NC_000001.10:g.27218912G>A`, `NC_000001.11:g.26892421G>A`, `NM_022078.3:c.1351C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1792)
- REVEL 0.355 (indeterminate)
- SaProt LLR -10.241 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 8.633, GERP 0.294, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 31.0**. 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 0.99** across the covering region of the MANE Select transcript (26,891,013–26,900,442), spanning 9,429 bp. Chi-square p 0.78. 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>C, Δ0.23 donor 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 **0.00223%** (eas) · FAF95 0.000124% · FAF99 9e-05% · 1/44,836 in the highest group · 7/1,612,710 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,836 |
| South Asian | 0.0011% | 91,050 |
| European (non-Finnish) | 0.000424% | 235,856 |

*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}

**GPATCH3** population constraint: LOEUF 1.009, pLI 6.0839e-13, missense-Z 0.66974. *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 **451** lies in the g-patch domain.

AlphaFold model confidence (whole protein): pLDDT 68.01, 3% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-07.

**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 | 2025-08-07 |

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

## Similar variants {#similar}

Related GPATCH3 variant pages (same residue, condition, or type): [GPATCH3 p.Arg451His](/variant/gpatch3-p-arg451his), [GPATCH3 p.Ala254Thr](/variant/gpatch3-p-ala254thr), [GPATCH3 p.Ala27Ser](/variant/gpatch3-p-ala27ser), [GPATCH3 p.Ala342Val](/variant/gpatch3-p-ala342val), [GPATCH3 p.Arg109Lys](/variant/gpatch3-p-arg109lys), [GPATCH3 p.Arg124Cys](/variant/gpatch3-p-arg124cys), [GPATCH3 p.Arg160Gln](/variant/gpatch3-p-arg160gln), [GPATCH3 p.Arg192Gly](/variant/gpatch3-p-arg192gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4265405). 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.*