Is TPH2 p.Pro206Ser (c.616C>T) pathogenic?

TPH2 p.Pro206Ser (c.616C>T) is classified Uncertain significance in TPH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-12-09). AlphaMissense: likely benign (0.1586); Rare (popmax 0.172%, sas); Associated with major depressive disorder.

What condition is associated with TPH2 p.Pro206Ser (c.616C>T)?

TPH2 p.Pro206Ser (c.616C>T) is associated with major depressive disorder, attention deficit-hyperactivity disorder, susceptibility to, 7 (ClinVar).

How common is TPH2 p.Pro206Ser (c.616C>T) in the general population?

TPH2 p.Pro206Ser (c.616C>T) is rare (popmax 0.172%, sas) (gnomAD).

What do computational predictors say about TPH2 p.Pro206Ser (c.616C>T)?

AlphaMissense predicts likely benign (score 0.1586) — an in-silico prediction, not a clinical call.

TPH2 p.Pro206Ser

c.616C>T · rs17110563 · VCV3164

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1586 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.172%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

major depressive disorder

Computational evidence

Protein change
AlphaMissense	0.1586	likely benign
REVEL	0.694	pathogenic-leaning
SaProt	LLR -9.27	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.172% South Asian · 157/91,068 alleles

Filtering AF 0.164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.162%

Overall 0.149% 2,403/1,614,092 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.172%	580
European (non-Finnish)	0.171%	586
Admixed American	0.133%	750
Remaining individualsnot grpmax-eligible	0.125%	801
Ashkenazi Jewishnot grpmax-eligible	0.0676%	1,480
Middle Eastern	0.066%	1,516
African / African-American	0.036%	2,779
Finnishnot grpmax-eligible	0.0359%	2,784

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.Pro206Ser
Coding: c.616C>T
MANE Select: NM_005651 · reported on NM_173353
dbSNP: rs17110563
Type: single nucleotide variant
Location: chr12:71972526 (GRCh38)
Structure: AlphaFold pLDDT 90.63 · 22 PDB
Residue 206: an α-helix

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

Disease context

major depressive disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: attention deficit-hyperactivity disorder, susceptibility to, 7

Similar variants

TPH2 p.Ser41Tyr Likely benign ★★ same condition
TPH2 p.Ala328Gly Uncertain significance ★ ⚠ same condition
TPH2 p.Arg237Gln Uncertain significance ★ ⚠ same condition
TDO2 p.Val306= Benign/Likely benign ★★ same type
TPH2 c.-52A>G Benign ★★ same type
TPH2 c.*149G>A Likely benign ★★ same type
TPH2 c.*479G>A Benign ★★ same type
TPH2 p.Ala375= Benign ★★ same type

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-pro206ser (accessed [today's date]).

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