# NM_018040.5(GPATCH2):c.1378G>A (p.Glu460Lys)

https://sugi.bio/variant/gpatch2-p-glu460lys

## Summary

**GPATCH2 p.Glu460Lys (c.1378G>A)** is classified **Uncertain significance** in GPATCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.2688); Very rare (popmax 0.000263%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000263%, nfe)

## For patients & families {#patients}

This is a change in the GPATCH2 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 | [GPATCH2](https://sugi.bio/atlas/gene/GPATCH2/) |
| Protein change (HGVS p.) | p.Glu460Lys |
| Coding change (HGVS c.) | c.1378G>A |
| MANE Select transcript | [NM_018040](https://www.ncbi.nlm.nih.gov/nuccore/NM_018040) |
| Variant type | single nucleotide variant |
| Location | chr1:217431354-217431354 (GRCh38) |
| ClinVar | [VCV4265377](https://www.ncbi.nlm.nih.gov/clinvar/variation/4265377/) |

**All HGVS expressions:** `NC_000001.10:g.217604696C>T`, `NC_000001.11:g.217431354C>T`, `NG_053034.1:g.204749G>A`, `NM_018040.5:c.1378G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2688)
- REVEL 0.177 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.948 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.631, GERP 1.83, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.0**. 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 0.96** across the covering region of the MANE Select transcript (217,431,148–217,630,971), spanning 199,823 bp. Chi-square p 0.29. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.23**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.23**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.000263%** (nfe) · FAF95 7e-05% · FAF99 1.9e-05% · 3/1,140,412 in the highest group · 3/1,570,708 alleles overall — very rare (popmax 0.000263%, nfe).

*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}

**GPATCH2** population constraint: LOEUF 1.233, pLI 5.1658e-08, missense-Z 0.53042. *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 55.60, 6% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-10.

**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 | 2025-09-10 |

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

## Similar variants {#similar}

Related GPATCH2 variant pages (same residue, condition, or type): [GPATCH2 p.Ala396Val](/variant/gpatch2-p-ala396val), [GPATCH2 p.Arg126His](/variant/gpatch2-p-arg126his), [GPATCH2 p.Arg137Gln](/variant/gpatch2-p-arg137gln), [GPATCH2 p.Arg159Cys](/variant/gpatch2-p-arg159cys), [GPATCH2 p.Arg212Ile](/variant/gpatch2-p-arg212ile), [GPATCH2 p.Arg218Lys](/variant/gpatch2-p-arg218lys), [GPATCH2 p.Arg347Cys](/variant/gpatch2-p-arg347cys), [GPATCH2 p.Arg410Gln](/variant/gpatch2-p-arg410gln).

### 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 4265377). 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.*