# NM_000277.3(PAH):c.165del (p.Phe55fs)

https://sugi.bio/variant/pah-p-phe55fs

## Summary

**PAH p.Phe55fs (c.165del)** is classified **Pathogenic** in PAH (ClinVar, Expert panel, 14 submitters; last evaluated 2019-04-03). Very rare (popmax 0.00239%, nfe); Associated with phenylketonuria.

**At a glance:** Pathogenic · review: Expert panel · rsID rs199475566 · 14 submitters · 1 linked condition · very rare (popmax 0.00239%, nfe)

## For patients & families {#patients}

This is a change in the PAH gene that is considered disease-causing, submitted by 14 submitters, and is linked to phenylketonuria.

*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) | Infancy |
| Prevalence | 1-9 / 100 000 (France) |
| Clinical trials | 176 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PAH is a diagnostic-grade gene on 11 Genomics England panels |

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

- Phenylalaninuria — Very frequent (99-80%)
- Microcephaly — Frequent (79-30%)
- Atypical behavior — Frequent (79-30%)
- Osteopenia — Frequent (79-30%)
- Eczematoid dermatitis — Frequent (79-30%)
- Hypopigmentation of the skin — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Global developmental delay — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007383/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PAH](https://sugi.bio/atlas/gene/PAH/) |
| Protein change (HGVS p.) | p.Phe55fs |
| Coding change (HGVS c.) | c.165del |
| MANE Select transcript | [NM_000277](https://www.ncbi.nlm.nih.gov/nuccore/NM_000277) |
| dbSNP | [rs199475566](https://www.ncbi.nlm.nih.gov/snp/rs199475566/) |
| Variant type | Deletion |
| Location | chr12:102912794-102912794 (GRCh38) |
| ClinVar | [VCV611](https://www.ncbi.nlm.nih.gov/clinvar/variation/611/) |

**All HGVS expressions:** `NC_000012.11:g.103306574del`, `NC_000012.12:g.102912796del`, `NG_008690.2:g.50617del`, `NM_000277.2:c.165delT`, `NM_000277.3:c.165del`, `NM_000277.3:c.165delT`, `NM_001354304.2:c.165del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 7.695, GERP 2, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.265, pLI 9.0947e-20. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 13**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 26.1**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00239%** (nfe) · FAF95 0.00166% · FAF99 0.00143% · 28/1,170,792 in the highest group · 29/1,603,814 alleles overall — very rare (popmax 0.00239%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00239% | 41,814 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,146 |

*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}

**PAH** population constraint: LOEUF 1.265, pLI 9.0947e-20, missense-Z -0.00030735; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **phenylketonuria** — Definitive (AR)

## Protein context {#protein}

Residue **55** lies in the act domain; a UniProt-annotated variant site (in pah deficiency; does not affect oligomerization; results in loss of substrate activation); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 89.04, 63% of residues very-high.

**21 experimental structure(s)** (PDB): [1DMW](https://www.rcsb.org/structure/1DMW), [1J8T](https://www.rcsb.org/structure/1J8T), [1J8U](https://www.rcsb.org/structure/1J8U), [1KW0](https://www.rcsb.org/structure/1KW0), [1LRM](https://www.rcsb.org/structure/1LRM), [1MMK](https://www.rcsb.org/structure/1MMK) — incl. mutant structure 1TDW.

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

*Describes the biological roles of PAH (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:** PAH's established molecular role includes phenylalanine 4-monooxygenase activity. p.Phe55fs falls in the act domain. In Reactome, PAH is annotated in disease pathway(s) including **Phenylketonuria**.

**Disease mechanism (Reactome):** PAH loss or alteration is curated in [Phenylketonuria](https://reactome.org/content/detail/R-HSA-2160456).

### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Phenylketonuria](https://reactome.org/content/detail/R-HSA-2160456) | curated |
| [Phenylalanine metabolism](https://reactome.org/content/detail/R-HSA-8964208) | curated |

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

**Molecular function:** phenylalanine 4-monooxygenase activity.

## Clinical significance {#significance}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2019-04-03.

**Submitter consensus:** conflicting (13 Pathogenic, 1 not provided).

**Submission history:** 14 submissions (1991–2026); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — Phenylketonuria VCEP (phenylketonuria). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2`, `PVS1`, `PP4`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.165delT (p.F55Lfs*6) is a frameshift variant in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in compound heterozygote state in multiple patients with PKU (BH4 deficiency not excluded) (PMID: 1682235 & 23500595). The variants in trans include: R408W, and R261Q, both confirmed pathogenic.This variant has an extremely low allele frequency in the Genome Aggregation database (3/251384) (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria: PM2, PP4, PVS1.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50015 · approved 2019-04-03 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/71884bd5-9f73-46c5-ad77-5b47444367a9).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2026-05-08 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2019-07-10 |
| DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | not provided | no classification provided | not provided |  |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1991-10-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2016-11-03 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Pathogenic | criteria provided, single submitter | clinical testing | 2016-12-05 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-22 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2013-08-27 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-10 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-01 |
| ClinGen PAH Variant Curation Expert Panel | Pathogenic | reviewed by expert panel | curation | 2019-04-03 |
| Counsyl | Pathogenic | no assertion criteria provided | clinical testing | 2019-07-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-17 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-24 |

## Associated conditions {#conditions}

[phenylketonuria](https://sugi.bio/atlas/disease/phenylketonuria/).

**Reported phenotype names (ClinVar):** Phenylketonuria, not provided, PAH-related disorder, PAH-related condition, none provided, OLIGOPHRENIA PHENYLPYRUVICA, FOLLING DISEASE, Phenylalanine Hydroxylase Deficiency, Phenylketonurias.

## Same-residue context {#hotspot}

Residue **55** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [PAH p.Phe55del](/variant/pah-p-phe55del), [PAH p.Phe55Ser](/variant/pah-p-phe55ser), [PAH p.Phe55Leu](/variant/pah-p-phe55leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PAH variant pages (same residue, condition, or type): [PAH p.Phe55del](/variant/pah-p-phe55del), [PAH p.Phe55Ser](/variant/pah-p-phe55ser), [PAH p.Phe55Leu](/variant/pah-p-phe55leu), [PAH p.Phe55=](/variant/pah-p-phe55), [PAH c.1200-1delG](/variant/pah-c-1200-minus-1delg), [PAH c.1314_1315+4del](/variant/pah-c-1314-1315-plus-4del), [PAH c.169_171del](/variant/pah-c-169-171del), [PAH c.442-1377_509+226del](/variant/pah-c-442-minus-1377-509-plus-226del).

### 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 611). 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.*