# NM_000277.3(PAH):c.1096C>T (p.Pro366Ser)

https://sugi.bio/variant/pah-p-pro366ser

## Summary

**PAH p.Pro366Ser (c.1096C>T)** is classified **Likely pathogenic** in PAH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). AlphaMissense: likely benign (0.1392); Very rare (popmax 0.00133%, afr); Associated with phenylketonuria.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2136635839 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the PAH gene that is considered likely disease-causing, submitted by 1 submitter, 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.Pro366Ser |
| Coding change (HGVS c.) | c.1096C>T |
| MANE Select transcript | [NM_000277](https://www.ncbi.nlm.nih.gov/nuccore/NM_000277) |
| dbSNP | [rs2136635839](https://www.ncbi.nlm.nih.gov/snp/rs2136635839/) |
| Variant type | single nucleotide variant |
| Location | chr12:102843749-102843749 (GRCh38) |
| ClinVar | [VCV1067076](https://www.ncbi.nlm.nih.gov/clinvar/variation/1067076/) |

**All HGVS expressions:** `NC_000012.11:g.103237527G>A`, `NC_000012.12:g.102843749G>A`, `NG_008690.2:g.119662C>T`, `NM_000277.3:c.1096C>T`, `NM_001354304.2:c.1096C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.1392) — ⚠ discordant with the pathogenic call
- REVEL 0.664 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -11.141 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 7.549, GERP 0.032, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.4**. 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 1.07** across the covering region of the MANE Select transcript (102,839,178–102,917,130), spanning 77,952 bp. Chi-square p 0.12. 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 **0.00133%** (afr) · FAF95 0.000359% · FAF99 0.00026% · 1/74,964 in the highest group · 10/1,461,426 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00133% | 74,964 |
| European (non-Finnish) | 0.000763% | 131,072 |

*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 30, triplosensitivity 0 (0–3 scale). *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 **366** lies in a UniProt-annotated variant site (in pah deficiency; severe); a β-strand.

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. 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-31.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-07-31 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Phenylketonuria, FOLLING DISEASE, Phenylketonurias, Phenylalanine Hydroxylase Deficiency, OLIGOPHRENIA PHENYLPYRUVICA.

## Same-residue context {#hotspot}

Residue **366** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PAH p.Pro366His](/variant/pah-p-pro366his). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PAH variant pages (same residue, condition, or type): [PAH p.Pro366His](/variant/pah-p-pro366his), [PAH p.Pro366Ala](/variant/pah-p-pro366ala), [PAH p.Pro366Leu](/variant/pah-p-pro366leu), [PAH p.Pro366=](/variant/pah-p-pro366), [PAH c.1065+1G>A](/variant/pah-c-1065-plus-1g-a), [PAH c.1065+1G>T](/variant/pah-c-1065-plus-1g-t), [PAH c.1065+3A>G](/variant/pah-c-1065-plus-3a-g), [PAH c.1066-11G>A](/variant/pah-c-1066-minus-11g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1067076). 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.*