# NM_006214.4(PHYH):c.546C>G (p.Pro182=)

https://sugi.bio/variant/phyh-p-pro182

## Summary

**PHYH p.Pro182= (c.546C>G)** is classified **Likely benign** in PHYH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-22). Absent from gnomAD v4.1.

**At a glance:** Likely benign · review: Single submitter · rsID rs747694906 · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PHYH 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 | [PHYH](https://sugi.bio/atlas/gene/PHYH/) |
| Protein change (HGVS p.) | p.Pro182= |
| Coding change (HGVS c.) | c.546C>G |
| MANE Select transcript | [NM_006214](https://www.ncbi.nlm.nih.gov/nuccore/NM_006214) |
| dbSNP | [rs747694906](https://www.ncbi.nlm.nih.gov/snp/rs747694906/) |
| Variant type | single nucleotide variant |
| Location | chr10:13288492-13288492 (GRCh38) |
| ClinVar | [VCV2696784](https://www.ncbi.nlm.nih.gov/clinvar/variation/2696784/) |

**All HGVS expressions:** `NC_000010.10:g.13330492G>C`, `NC_000010.11:g.13288492G>C`, `NG_012862.1:g.16639C>G`, `NM_001037537.2:c.246C>G`, `NM_001323080.2:c.246C>G`, `NM_001323082.2:c.552C>G`, `NM_001323083.2:c.415-4653C>G`, `NM_001323084.2:c.252C>G`, `NM_006214.4:c.546C>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 loss** (Δ 0.32) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.084, GERP -0.507, phastCons 0.171 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.118**. 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 **0.32**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**. Largest is acceptor loss, 6 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**PHYH** population constraint: LOEUF 1.147, pLI 1.4384e-06, missense-Z 0.45192. *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):

- **phytanoyl-CoA hydroxylase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.33, 68% of residues very-high.

**1 experimental structure(s)** (PDB): [2A1X](https://www.rcsb.org/structure/2A1X).

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

*Describes the biological roles of PHYH (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:** PHYH's established molecular role includes ferrous iron binding.


### Pathways affected {#pathways}

PHYH participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Alpha-oxidation of phytanate](https://reactome.org/content/detail/R-HSA-389599) | curated |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |
| [TYSND1 cleaves peroxisomal proteins](https://reactome.org/content/detail/R-HSA-9033500) | electronic |

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

**Molecular function:** ferrous iron binding, carboxylic acid binding, L-ascorbic acid binding, phytanoyl-CoA dioxygenase activity.

**Biological process:** fatty acid alpha-oxidation, 2-oxoglutarate metabolic process, isoprenoid metabolic process, methyl-branched fatty acid metabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-22.

**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 | 2023-11-22 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related PHYH variant pages (same residue, condition, or type): [PHYH p.Pro182Ala](/variant/phyh-p-pro182ala), [PHYH c.134+1G>A](/variant/phyh-c-134-plus-1g-a), [PHYH c.135-1G>C](/variant/phyh-c-135-minus-1g-c), [PHYH c.135-2A>G](/variant/phyh-c-135-minus-2a-g), [PHYH c.497-1G>A](/variant/phyh-c-497-minus-1g-a), [PHYH c.497-2A>G](/variant/phyh-c-497-minus-2a-g), [PHYH c.678+2T>C](/variant/phyh-c-678-plus-2t-c), [PHYH p.Ala277Glu](/variant/phyh-p-ala277glu).

### 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 2696784). 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.*