Is TPH2 p.Ala342Val (c.1025C>T) pathogenic?

TPH2 p.Ala342Val (c.1025C>T) is classified Uncertain significance in TPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: likely pathogenic (0.6311); Very rare (popmax 0.00333%, amr).

How common is TPH2 p.Ala342Val (c.1025C>T) in the general population?

TPH2 p.Ala342Val (c.1025C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about TPH2 p.Ala342Val (c.1025C>T)?

AlphaMissense predicts likely pathogenic (score 0.6311) — an in-silico prediction, not a clinical call.

TPH2 p.Ala342Val

c.1025C>T · VCV3972614

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6311 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6311	likely pathogenic
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -11.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,982 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00248% 40/1,613,782 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,991
European (non-Finnish)	0.00305%	32,773
East Asian	0.00223%	44,878
African / African-American	0.00133%	74,910

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.Ala342Val
Coding: c.1025C>T
MANE Select: NM_005651 · reported on NM_173353
Type: single nucleotide variant
Location: chr12:71994522 (GRCh38)
Structure: AlphaFold pLDDT 90.63 · 22 PDB
Residue 342: a binding site; a β-strand

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

Similar variants

TPH2 p.Pro206Ser Uncertain significance ★★ ⚠ same type
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
TPH2 p.Leu36Val Benign/Likely benign ★★ same type
TPH2 p.Pro180= Benign/Likely 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-ala342val (accessed [today's date]).

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