# NM_001396855.1(GPATCH4):c.161A>G (p.His54Arg)

https://sugi.bio/variant/gpatch4-p-his54arg

## Summary

**GPATCH4 p.His54Arg (c.161A>G)** is classified **Uncertain significance** in GPATCH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-02). Ultra-rare (popmax 0.0196%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs369352887 · 1 submitter · ultra-rare (popmax 0.0196%, nfe)

## For patients & families {#patients}

This is a change in the GPATCH4 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 | [GPATCH4](https://sugi.bio/atlas/gene/GPATCH4/) |
| Protein change (HGVS p.) | p.His54Arg |
| Coding change (HGVS c.) | c.161A>G |
| dbSNP | [rs369352887](https://www.ncbi.nlm.nih.gov/snp/rs369352887/) |
| Variant type | single nucleotide variant |
| Location | chr1:156598312-156598312 (GRCh38) |
| ClinVar | [VCV3101174](https://www.ncbi.nlm.nih.gov/clinvar/variation/3101174/) |

**All HGVS expressions:** `NC_000001.10:g.156568104T>C`, `NC_000001.11:g.156598312T>C`, `NM_001396855.1:c.161A>G`, `NM_001396861.1:c.176A>G`, `NM_015590.4:c.176A>G`, `NM_182679.3:c.161A>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.805, GERP 2.57, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 28.3**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**. Largest is acceptor gain, 3 bp away.
  These are **raw** scores. Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — can legitimately show 0 where this shows a score; the masked figures are not available for this record.
- Population frequency (gnomAD v4.1): grpmax **0.0196%** (nfe) · FAF95 0.0175% · FAF99 0.0166% · 229/1,169,560 in the highest group · 240/1,594,256 alleles overall — ultra-rare (popmax 0.0196%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0196% | 5,107 |
| Remaining individuals (not grpmax-eligible) | 0.0162% | 6,168 |
| African / African-American | 0.00134% | 74,582 |

*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}

**GPATCH4** population constraint: LOEUF 1.669, pLI 2.2059e-08, missense-Z 1.1672. *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 **54** lies in the g-patch domain.

AlphaFold model confidence (whole protein): pLDDT 57.52, 12% of residues very-high.

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

*Describes the biological roles of GPATCH4 (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:** GPATCH4's established molecular role includes RNA binding. p.His54Arg falls in the g-patch domain.


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

**Molecular function:** RNA binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-02.

**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 | 2024-02-02 |

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

## Similar variants {#similar}

Related GPATCH4 variant pages (same residue, condition, or type): [GPATCH4 p.Thr54Ile](/variant/gpatch4-p-thr54ile), [GPATCH4 c.348+115G>A](/variant/gpatch4-c-348-plus-115g-a), [GPATCH4 c.-65A>C](/variant/gpatch4-c-minus-65a-c), [GPATCH4 c.-74G>C](/variant/gpatch4-c-minus-74g-c), [GPATCH4 c.-79G>C](/variant/gpatch4-c-minus-79g-c), [GPATCH4 p.Ala162Thr](/variant/gpatch4-p-ala162thr), [GPATCH4 p.Ala174Pro](/variant/gpatch4-p-ala174pro), [GPATCH4 p.Ala219Val](/variant/gpatch4-p-ala219val).

### 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 3101174). 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.*