# NM_001396855.1(GPATCH4):c.64C>T (p.His22Tyr)

https://sugi.bio/variant/gpatch4-p-his22tyr

## Summary

**GPATCH4 p.His22Tyr (c.64C>T)** is classified **Uncertain significance** in GPATCH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). Very rare (popmax 0.00992%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs745392006 · 1 submitter · very rare (popmax 0.00992%, 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.His22Tyr |
| Coding change (HGVS c.) | c.64C>T |
| dbSNP | [rs745392006](https://www.ncbi.nlm.nih.gov/snp/rs745392006/) |
| Variant type | single nucleotide variant |
| Location | chr1:156598983-156598983 (GRCh38) |
| ClinVar | [VCV2232333](https://www.ncbi.nlm.nih.gov/clinvar/variation/2232333/) |

**All HGVS expressions:** `NC_000001.10:g.156568775G>A`, `NC_000001.11:g.156598983G>A`, `NM_001396855.1:c.64C>T`, `NM_001396861.1:c.79C>T`, `NM_015590.4:c.79C>T`, `NM_182679.3:c.64C>T`

## 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 **donor gain** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.394, GERP 2.57, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 24.6**. 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 **0.10**, donor loss **0.06**, acceptor gain **0.00**, donor gain **0.22**. Largest is donor gain, 2 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.
- Pangolin: Δ**0.30** (gain), gain 0.30 / loss 0.11. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00992%** (nfe) · FAF95 0.00842% · FAF99 0.00787% · 117/1,179,948 in the highest group · 121/1,613,926 alleles overall — very rare (popmax 0.00992%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00992% | 10,085 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,829 |
| African / African-American | 0.00133% | 74,908 |

*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 **22** 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.His22Tyr 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 2025-08-06.

**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 | 2025-08-06 |

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

## Similar variants {#similar}

Related GPATCH4 variant pages (same residue, condition, or type): [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), [GPATCH4 p.Ala316Val](/variant/gpatch4-p-ala316val).

### 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 2232333). 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.*