Is TPH2 p.Ile439Val (c.1315A>G) pathogenic?

TPH2 p.Ile439Val (c.1315A>G) is classified Uncertain significance in TPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-12). AlphaMissense: likely benign (0.1319); Very rare (popmax 0.00331%, nfe).

How common is TPH2 p.Ile439Val (c.1315A>G) in the general population?

TPH2 p.Ile439Val (c.1315A>G) is very rare (popmax 0.00331%, nfe) (gnomAD).

What do computational predictors say about TPH2 p.Ile439Val (c.1315A>G)?

AlphaMissense predicts likely benign (score 0.1319) — an in-silico prediction, not a clinical call.

TPH2 p.Ile439Val

c.1315A>G · VCV3460482

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1319 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1319	likely benign
REVEL	0.653	pathogenic-leaning
SaProt	LLR -8.05	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 9.4	GERP 1.9, phastCons 1
Overall
CADD	22.9	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 0.00331% European (non-Finnish) · 39/1,179,666 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00248% 40/1,613,582 alleles · very rare exomes 40/1,461,354 · genomes 0/152,228 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00331%	30,248
East Asian	0.00223%	44,860

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.Ile439Val
Coding: c.1315A>G
MANE Select: NM_173353
Type: single nucleotide variant
Location: chr12:72031537 (GRCh38)
Structure: AlphaFold pLDDT 90.63 · 22 PDB

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

Similar variants

TPH2 p.Ile439Phe Uncertain significance ★ ⚠ same residue
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

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-ile439val (accessed [today's date]).

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