Is TPH2 p.Pro312= (c.936A>G) pathogenic?

TPH2 p.Pro312= (c.936A>G) is classified Benign in TPH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-03-06). Common (popmax 60.2%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Tryptophan 5-monooxygenase deficiency.

What condition is associated with TPH2 p.Pro312= (c.936A>G)?

TPH2 p.Pro312= (c.936A>G) is associated with Tryptophan 5-monooxygenase deficiency (ClinVar).

TPH2 p.Pro312=

Q: How common is TPH2 p.Pro312= (c.936A>G) in the general population?

TPH2 p.Pro312= (c.936A>G) is common (popmax 60.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.936A>G · rs7305115 · VCV310386

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 60.2%, afr) — 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 -9.4	GERP -3.7
Overall
CADD	0.015	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 60.2% African / African-American · 45,072/74,884 alleles

Filtering AF 59.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 59.5%

Overall 57% 920,002/1,613,674 alleles · common exomes 832,204/1,461,714 · genomes 87,798/151,960 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	63.9%	2
Amishnot grpmax-eligible	63%	2
African / African-Americangrpmax	60.2%	2
Middle Eastern	58.6%	2
European (non-Finnish)	57.4%	2
Finnishnot grpmax-eligible	57.3%	2
Remaining individualsnot grpmax-eligible	56.7%	2
South Asian	52.9%	2
Admixed American	52.6%	2
East Asian	50.6%	2

Ashkenazi Jewish 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.Pro312=
Coding: c.936A>G
MANE Select: NM_173353
dbSNP: rs7305115
Type: single nucleotide variant
Location: chr12:71979082 (GRCh38)
Structure: AlphaFold pLDDT 90.63 · 22 PDB
Residue 312: 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.Ala375= Benign ★★ same condition
TPH2 p.Leu36Val Benign/Likely benign ★★ same condition
TPH2 p.Pro180= Benign/Likely 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-pro312 (accessed [today's date]).

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