# NM_002863.5(PYGL):c.1266T>C (p.Asp422=)

https://sugi.bio/variant/pygl-p-asp422

## Summary

**PYGL p.Asp422= (c.1266T>C)** is classified **Likely benign** in PYGL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-02). Very rare (popmax 0.000847%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs1427302108 · 1 submitter · very rare (popmax 0.000847%, nfe)

## For patients & families {#patients}

This is a change in the PYGL gene that is classified as likely benign — not considered disease-causing, 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 | [PYGL](https://sugi.bio/atlas/gene/PYGL/) |
| Protein change (HGVS p.) | p.Asp422= |
| Coding change (HGVS c.) | c.1266T>C |
| MANE Select transcript | [NM_002863](https://www.ncbi.nlm.nih.gov/nuccore/NM_002863) |
| dbSNP | [rs1427302108](https://www.ncbi.nlm.nih.gov/snp/rs1427302108/) |
| Variant type | single nucleotide variant |
| Location | chr14:50915473-50915473 (GRCh38) |
| ClinVar | [VCV743133](https://www.ncbi.nlm.nih.gov/clinvar/variation/743133/) |

**All HGVS expressions:** `NC_000014.8:g.51382191A>G`, `NC_000014.9:g.50915473A>G`, `NG_012796.1:g.34058T>C`, `NM_001163940.2:c.1164T>C`, `NM_002863.5:c.1266T>C`

## 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 loss** (Δ 0.23) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.108, GERP -3.89 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.164**. 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 **0.23**, donor loss **0.00**, acceptor gain **0.06**, donor gain **0.00**. Largest is acceptor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.06**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.000847%** (nfe) · FAF95 0.000429% · FAF99 0.000312% · 10/1,180,040 in the highest group · 10/1,614,204 alleles overall — very rare (popmax 0.000847%, 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}

**PYGL** population constraint: LOEUF 1.048, pLI 4.2298e-27, missense-Z 0.96944. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **glycogen storage disease VI** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.87, 87% of residues very-high.

**19 experimental structure(s)** (PDB): [1EM6](https://www.rcsb.org/structure/1EM6), [1EXV](https://www.rcsb.org/structure/1EXV), [1FA9](https://www.rcsb.org/structure/1FA9), [1FC0](https://www.rcsb.org/structure/1FC0), [1L5Q](https://www.rcsb.org/structure/1L5Q), [1L5R](https://www.rcsb.org/structure/1L5R).

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

*Describes the biological roles of PYGL (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:** PYGL's established molecular role includes purine nucleobase binding.


### Pathways affected {#pathways}

PYGL participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycogen breakdown (glycogenolysis)](https://reactome.org/content/detail/R-HSA-70221) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

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

**Molecular function:** purine nucleobase binding, ATP binding, D-glucose binding, glycogen phosphorylase activity, AMP binding, vitamin binding.

**Biological process:** glycogen metabolic process, glucose homeostasis.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-05-02.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2018-05-02 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related PYGL variant pages (same residue, condition, or type): [PYGL p.Asp422Val](/variant/pygl-p-asp422val), [PYGL c.1404-1G>A](/variant/pygl-c-1404-minus-1g-a), [PYGL c.1620+1G>A](/variant/pygl-c-1620-plus-1g-a), [PYGL c.1620+1G>C](/variant/pygl-c-1620-plus-1g-c), [PYGL c.1768+1G>A](/variant/pygl-c-1768-plus-1g-a), [PYGL c.772+1G>A](/variant/pygl-c-772-plus-1g-a), [PYGL p.Arg576Ter](/variant/pygl-p-arg576ter), [PYGL p.Arg94Ter](/variant/pygl-p-arg94ter).

### 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 743133). 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.*