Is TPH1 p.Arg230Cys (c.688C>T) pathogenic?

TPH1 p.Arg230Cys (c.688C>T) is classified Uncertain significance in TPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-25). AlphaMissense: likely pathogenic (0.7578); Ultra-rare (popmax 0.01%, amr).

How common is TPH1 p.Arg230Cys (c.688C>T) in the general population?

TPH1 p.Arg230Cys (c.688C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about TPH1 p.Arg230Cys (c.688C>T)?

AlphaMissense predicts likely pathogenic (score 0.7578) — an in-silico prediction, not a clinical call.

TPH1 p.Arg230Cys

c.688C>T · VCV3972610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7578 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7578	likely pathogenic
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -10.25	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 20 kb · p 0.11 · regional, not allelic
Overall
CADD	33.0	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 0.01% Admixed American · 6/59,972 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00297% 48/1,613,878 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,995
South Asian	0.00878%	11,383
Remaining individualsnot grpmax-eligible	0.0032%	31,240
European (non-Finnish)	0.00263%	38,064
African / African-American	0.00134%	74,888

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.Arg230Cys
Coding: c.688C>T
MANE Select: NM_004179
Type: single nucleotide variant
Location: chr11:18026605 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.96 · 21 PDB
Residue 230: a β-strand

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.Arg395Cys 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-arg230cys (accessed [today's date]).

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