# NM_024854.5(PYROXD1):c.555C>T (p.Phe185=)

https://sugi.bio/variant/pyroxd1-p-phe185

## Summary

**PYROXD1 p.Phe185= (c.555C>T)** is classified **Benign** in PYROXD1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-18). Low-frequency (popmax 1.86%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs146792991 · 4 submitters · low-frequency (popmax 1.86%, afr)

## For patients & families {#patients}

This is a change in the PYROXD1 gene that is classified as benign — not considered disease-causing, submitted by 4 submitters.

*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 | [PYROXD1](https://sugi.bio/atlas/gene/PYROXD1/) |
| Protein change (HGVS p.) | p.Phe185= |
| Coding change (HGVS c.) | c.555C>T |
| MANE Select transcript | [NM_024854](https://www.ncbi.nlm.nih.gov/nuccore/NM_024854) |
| dbSNP | [rs146792991](https://www.ncbi.nlm.nih.gov/snp/rs146792991/) |
| Variant type | single nucleotide variant |
| Location | chr12:21455198-21455198 (GRCh38) |
| ClinVar | [VCV729181](https://www.ncbi.nlm.nih.gov/clinvar/variation/729181/) |

**All HGVS expressions:** `NC_000012.11:g.21608132C>T`, `NC_000012.12:g.21455198C>T`, `NG_053196.1:g.22595C>T`, `NM_001350912.2:c.342C>T`, `NM_001350913.2:c.-223C>T`, `NM_024854.5:c.555C>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 **acceptor gain** (Δ 0.25) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -9.725, GERP -3.81 — fast-evolving / accelerated position
- CADD: **PHRED 13.99**. 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 **0.25**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.25**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **1.86%** (afr) · FAF95 1.78% · FAF99 1.75% · 1,365/73,378 in the highest group · 1,682/1,570,102 alleles overall — low-frequency (popmax 1.86%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.86% | 54 |
| Middle Eastern | 0.396% | 252 |
| Admixed American | 0.15% | 667 |
| Remaining individuals (not grpmax-eligible) | 0.143% | 700 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0211% | 4,733 |
| South Asian | 0.0178% | 5,632 |
| European (non-Finnish) | 0.00916% | 10,920 |
| East Asian | 0.00232% | 43,138 |

*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}

**PYROXD1** population constraint: LOEUF 1.107, pLI 3.8839e-05, missense-Z 1.0218. *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):

- **myofibrillar myopathy 8** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.64, 76% of residues very-high.

**2 experimental structure(s)** (PDB): [6ZK7](https://www.rcsb.org/structure/6ZK7), [8ORJ](https://www.rcsb.org/structure/8ORJ).

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

*Describes the biological roles of PYROXD1 (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:** PYROXD1's established molecular role includes NAD(P)H oxidase H2O2-forming activity.


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

**Molecular function:** NAD(P)H oxidase H2O2-forming activity, molecular sensor activity.

**Biological process:** tRNA exon ligation, cellular response to oxidative stress.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-18.

**Submitter consensus:** unanimous (4/4 Benign).

**Submission history:** 4 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-05-14 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2025-03-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-18 |

**Reported phenotype names (ClinVar):** not provided, PYROXD1-related disorder, not specified, PYROXD1-related condition, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related PYROXD1 variant pages (same residue, condition, or type): [PYROXD1 c.285+1G>A](/variant/pyroxd1-c-285-plus-1g-a), [PYROXD1 c.881-2A>T](/variant/pyroxd1-c-881-minus-2a-t), [PYROXD1 p.Asn155Ser](/variant/pyroxd1-p-asn155ser), [PYROXD1 p.Ala393Val](/variant/pyroxd1-p-ala393val), [PYROXD1 p.Arg132Cys](/variant/pyroxd1-p-arg132cys), [PYROXD1 p.Arg455Gln](/variant/pyroxd1-p-arg455gln), [PYROXD1 p.Arg76Cys](/variant/pyroxd1-p-arg76cys), [PYROXD1 p.Asn52Asp](/variant/pyroxd1-p-asn52asp).

### 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 729181). 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.*