Is TPH2 p.Ala375= (c.1125A>T) pathogenic?

TPH2 p.Ala375= (c.1125A>T) is classified Benign in TPH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-03-06). Common (popmax 64.5%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Tryptophan 5-monooxygenase deficiency.

What condition is associated with TPH2 p.Ala375= (c.1125A>T)?

TPH2 p.Ala375= (c.1125A>T) is associated with Tryptophan 5-monooxygenase deficiency (ClinVar).

TPH2 p.Ala375=

Q: How common is TPH2 p.Ala375= (c.1125A>T) in the general population?

TPH2 p.Ala375= (c.1125A>T) is common (popmax 64.5%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1125A>T · rs4290270 · VCV310388

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 64.5%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

Tryptophan 5-monooxygenase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.1	GERP -3.7
Overall
CADD	1.272	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 64.5% European (non-Finnish) · 760,052/1,179,198 alleles

Filtering AF 64.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 64.3%

Overall 61.2% 986,857/1,612,974 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	66.7%	1
European (non-Finnish)grpmax	64.5%	2
Ashkenazi Jewishnot grpmax-eligible	61.8%	2
Remaining individualsnot grpmax-eligible	59.5%	2
Middle Eastern	59.5%	2
Finnishnot grpmax-eligible	53.1%	2
Admixed American	53%	2
East Asian	52.3%	2
South Asian	52%	2
African / African-American	40.8%	2

Amish 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.Ala375=
Coding: c.1125A>T
MANE Select: NM_005651 · reported on NM_173353
dbSNP: rs4290270
Type: single nucleotide variant
Location: chr12:72022455 (GRCh38)
Structure: AlphaFold pLDDT 90.63 · 22 PDB
Residue 375: an α-helix

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.Leu36Val Benign/Likely benign ★★ same condition
TPH2 p.Pro180= 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-ala375 (accessed [today's date]).

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