Is TPH2 p.Pro180= (c.540A>G) pathogenic?

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.

What condition is associated with TPH2 p.Pro180= (c.540A>G)?

TPH2 p.Pro180= (c.540A>G) is associated with Tryptophan 5-monooxygenase deficiency (ClinVar).

How common is TPH2 p.Pro180= (c.540A>G) in the general population?

TPH2 p.Pro180= (c.540A>G) is rare (popmax 0.17%, nfe) (gnomAD).

TPH2 p.Pro180=

c.540A>G · rs139968591 · VCV310383

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.17%, nfe)

Conditions

Tryptophan 5-monooxygenase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.31	donor gain at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.8	GERP -2.3, phastCons 0.96
Overall
CADD	11.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.17% European (non-Finnish) · 2,006/1,179,410 alleles

Filtering AF 0.164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.161%

Overall 0.199% 3,205/1,613,416 alleles · rare exomes 2,880/1,461,130 · genomes 325/152,286 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.68%	59
Remaining individualsnot 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 Jewishnot grpmax-eligible	0.00338%	29,590

Finnish shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TPH2
Protein: p.Pro180=
Coding: c.540A>G
MANE Select: NM_173353
dbSNP: rs139968591
Type: single nucleotide variant
Location: chr12:71944686 (GRCh38)
Structure: AlphaFold pLDDT 90.63 · 22 PDB

Full TPH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Tryptophan 5-monooxygenase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TPH2 c.-52A>G Benign ★★ same condition
TPH2 c.*149G>A Likely benign ★★ same condition
TPH2 c.*479G>A Benign ★★ same condition
TPH2 p.Ala375= Benign ★★ same condition
TPH2 p.Leu36Val Benign/Likely benign ★★ same condition
TPH2 p.Pro312= Benign ★★ same condition
TPH2 c.1164+7A>G Uncertain significance ★ same condition
TPH2 c.1298+14T>C Uncertain significance ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tph2-p-pro180 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown