# NM_173353.4(TPH2):c.540A>G (p.Pro180=)

https://sugi.bio/variant/tph2-p-pro180

## Summary

**TPH2 p.Pro180= (c.540A>G)** is classified **Benign/Likely benign** in TPH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-05-21). Rare (popmax 0.17%, nfe); Associated with Tryptophan 5-monooxygenase deficiency.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs139968591 · 2 submitters · 1 linked condition · rare (popmax 0.17%, nfe)

## For patients & families {#patients}

This is a change in the TPH2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Tryptophan 5-monooxygenase deficiency.

*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 | [TPH2](https://sugi.bio/atlas/gene/TPH2/) |
| Protein change (HGVS p.) | p.Pro180= |
| Coding change (HGVS c.) | c.540A>G |
| MANE Select transcript | [NM_173353](https://www.ncbi.nlm.nih.gov/nuccore/NM_173353) |
| dbSNP | [rs139968591](https://www.ncbi.nlm.nih.gov/snp/rs139968591/) |
| Variant type | single nucleotide variant |
| Location | chr12:71944686-71944686 (GRCh38) |
| ClinVar | [VCV310383](https://www.ncbi.nlm.nih.gov/clinvar/variation/310383/) |

**All HGVS expressions:** `NC_000012.11:g.72338466A>G`, `NC_000012.12:g.71944686A>G`, `NG_008279.1:g.10841A>G`, `NM_173353.4:c.540A>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 **donor gain** (Δ 0.31) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.797, GERP -2.32, phastCons 0.959 — weakly conserved position
- CADD: **PHRED 11.24**. 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 **0.00**, donor gain **0.31**. Largest is donor gain at this position.
- 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 (gnomAD v4.1): grpmax **0.17%** (nfe) · FAF95 0.164% · FAF99 0.161% · 2,006/1,179,410 in the highest group · 3,205/1,613,416 alleles overall — rare (popmax 0.17%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 1.68% | 59 |
| Remaining individuals (not grpmax-eligible) | 0.174% | 573 |
| European (non-Finnish) (grpmax) | 0.17% | 588 |
| African / African-American | 0.0107% | 9,375 |
| Admixed American | 0.00667% | 14,997 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,590 |

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}


Curated gene–disease validity (ClinGen):

- **familial hypertryptophanemia** — Limited (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.63, 82% of residues very-high.

**22 experimental structure(s)** (PDB): [4PW8](https://www.rcsb.org/structure/4PW8), [5TI9](https://www.rcsb.org/structure/5TI9), [5TIA](https://www.rcsb.org/structure/5TIA), [6A4I](https://www.rcsb.org/structure/6A4I), [6PYY](https://www.rcsb.org/structure/6PYY), [6PYZ](https://www.rcsb.org/structure/6PYZ).

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

*Describes the biological roles of TPH2 (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:** TPH2's established molecular role includes L-tryptophan 2,3-dioxygenase activity.


### Pathways affected {#pathways}

TPH2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Tryptophan catabolism](https://reactome.org/content/detail/R-HSA-71240) | curated |

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

**Molecular function:** L-tryptophan 2,3-dioxygenase activity, heme binding, identical protein binding.

**Biological process:** obsolete L-tryptophan catabolic process to L-kynurenine, protein homotetramerization.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-05-21.

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

**Submission history:** 2 submissions (2017–2018); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-05-21 |

## Associated conditions {#conditions}

[Tryptophan 5-monooxygenase deficiency](https://sugi.bio/atlas/disease/tryptophan-5-monooxygenase-deficiency/).

**Reported phenotype names (ClinVar):** Tryptophan 5-monooxygenase deficiency, not provided, none provided.

## Similar variants {#similar}

Related TPH2 variant pages (same residue, condition, or type): [TPH2 c.-52A>G](/variant/tph2-c-minus-52a-g), [TPH2 c.*149G>A](/variant/tph2-c-star-149g-a), [TPH2 c.*479G>A](/variant/tph2-c-star-479g-a), [TPH2 p.Ala375=](/variant/tph2-p-ala375), [TPH2 p.Leu36Val](/variant/tph2-p-leu36val), [TPH2 p.Pro312=](/variant/tph2-p-pro312), [TPH2 c.1164+7A>G](/variant/tph2-c-1164-plus-7a-g), [TPH2 c.1298+14T>C](/variant/tph2-c-1298-plus-14t-c).

### 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 310383). 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.*