Is TPH1 p.Ile32Val (c.94A>G) pathogenic?

TPH1 p.Ile32Val (c.94A>G) is classified Uncertain significance in TPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-24). AlphaMissense: likely benign (0.065); Ultra-rare (popmax 0.0333%, mid).

How common is TPH1 p.Ile32Val (c.94A>G) in the general population?

TPH1 p.Ile32Val (c.94A>G) is ultra-rare (popmax 0.0333%, mid) (gnomAD).

What do computational predictors say about TPH1 p.Ile32Val (c.94A>G)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

TPH1 p.Ile32Val

c.94A>G · rs141116226 · VCV2398961

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -5.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP -0.42, phastCons 0.99
Regional constraint	o/e 0.93	unconstrained · MANE · 20 kb · p 0.11 · regional, not allelic
Overall
CADD	7.197	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0333% Middle Eastern · 2/5,998 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.00211% 34/1,612,230 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0333%	2,999
African / African-American	0.032%	3,125
Remaining individualsnot grpmax-eligible	0.00481%	20,803
European (non-Finnish)	0.000424%	235,833

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: TPH1
Protein: p.Ile32Val
Coding: c.94A>G
MANE Select: NM_004179
dbSNP: rs141116226
Type: single nucleotide variant
Location: chr11:18040669 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.96 · 21 PDB
Residue 32: the act domain

Full TPH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TPH1 p.Leu365= Benign ★★ same type
TPH1 p.Arg144His Uncertain significance ★ ⚠ same type
TPH1 p.Arg145Gln Uncertain significance ★ ⚠ same type
TPH1 p.Arg17Thr Uncertain significance ★ ⚠ same type
TPH1 p.Arg191Ser Uncertain significance ★ ⚠ same type
TPH1 p.Arg224Cys Uncertain significance ★ ⚠ same type
TPH1 p.Arg224His Uncertain significance ★ ⚠ same type
TPH1 p.Arg230Cys Uncertain significance ★ ⚠ 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/tph1-p-ile32val (accessed [today's date]).

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