# NM_006214.4(PHYH):c.85C>T (p.Pro29Ser)

https://sugi.bio/variant/phyh-p-pro29ser

## Summary

**PHYH p.Pro29Ser (c.85C>T)** is classified **Benign** in PHYH (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.075); Common (popmax 18%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with adult Refsum disease.

**At a glance:** Benign · review: Multiple submitters · rsID rs28938169 · 14 submitters · 1 linked condition · AlphaMissense likely benign · common (popmax 18%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the PHYH gene that is classified as benign — not considered disease-causing, submitted by 14 submitters, and is linked to adult Refsum disease.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PHYH is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Adult Refsum disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Anosmia — Very frequent (99-80%)
- Abnormality of the eye — Very frequent (99-80%)
- Retinopathy — Very frequent (99-80%)
- Abnormality of vision — Very frequent (99-80%)
- Cataract — Very frequent (99-80%)
- Dry skin — Very frequent (99-80%)
- Ataxia — Very frequent (99-80%)
- Cardiomyopathy — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005691/index) · [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.Pro29Ser |
| Coding change (HGVS c.) | c.85C>T |
| MANE Select transcript | [NM_006214](https://www.ncbi.nlm.nih.gov/nuccore/NM_006214) |
| dbSNP | [rs28938169](https://www.ncbi.nlm.nih.gov/snp/rs28938169/) |
| Variant type | single nucleotide variant |
| Location | chr10:13298236-13298236 (GRCh38) |
| ClinVar | [VCV7582](https://www.ncbi.nlm.nih.gov/clinvar/variation/7582/) |

**All HGVS expressions:** `NC_000010.10:g.13340236G>A`, `NC_000010.11:g.13298236G>A`, `NG_012862.1:g.6895C>T`, `NM_001037537.2:c.-167+1184C>T`, `NM_001323080.2:c.-216C>T`, `NM_001323082.2:c.85C>T`, `NM_001323083.2:c.85C>T`, `NM_001323084.2:c.-167+1184C>T`, `NM_006214.4:c.85C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 18%, nfe) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.075)
- REVEL 0.375 (indeterminate)
- SaProt LLR -5.079 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 0.564, GERP 0.46 — weakly conserved position
- CADD: **PHRED 13.64**. 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.*
- Regional missense constraint: **o/e 0.98** across the covering region of the MANE Select transcript (13,278,304–13,300,042), spanning 21,738 bp. Chi-square p 0.67. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **18%** (nfe) · FAF95 18% · FAF99 17.9% · 209,541/1,161,678 in the highest group · 263,679/1,593,910 alleles overall — common (popmax 18%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 22.8% | 4 |
| European (non-Finnish) (grpmax) | 18% | 6 |
| Remaining individuals (not grpmax-eligible) | 15.2% | 7 |
| Ashkenazi Jewish (not grpmax-eligible) | 14.8% | 7 |
| African / African-American | 11.7% | 9 |
| Admixed American | 10.9% | 9 |
| Middle Eastern | 10.4% | 10 |
| South Asian | 10.1% | 10 |
| Amish (not grpmax-eligible) | 7.69% | 13 |
| East Asian | 1.53% | 66 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **29** lies in a UniProt-annotated variant site (in).

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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (13 Benign, 1 Likely benign).

**Submission history:** 14 submissions (2000–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | no assertion criteria provided | clinical testing |  |
| Mendelics | Benign | criteria provided, single submitter | clinical testing | 2019-05-28 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-09-05 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| OMIM | Benign | no assertion criteria provided | literature only | 2000-05-01 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2014-05-09 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | no assertion criteria provided | clinical testing | 2015-10-26 |
| SIB Swiss Institute of Bioinformatics | Benign | criteria provided, single submitter | curation | 2018-05-31 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-03-06 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-09-26 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |

## Associated conditions {#conditions}

[adult Refsum disease](https://sugi.bio/atlas/disease/adult-refsum-disease/).

**Reported phenotype names (ClinVar):** Phytanic acid storage disease, not provided, not specified, AllHighlyPenetrant, none provided, REFSUM DISEASE, CLASSIC, PHYTANIC ACID OXIDASE DEFICIENCY, PHYH-Related Refsum Disease, HEREDOPATHIA ATACTICA POLYNEURITIFORMIS, HMSN IV.

## Similar variants {#similar}

Related PHYH variant pages (same residue, condition, or type): [PHYH p.Pro29=](/variant/phyh-p-pro29), [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 2026-10-14); 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 7582). 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.*