Is TPH1 p.Arg191Ser (c.573A>C) pathogenic?

TPH1 p.Arg191Ser (c.573A>C) is classified Uncertain significance in TPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-24). AlphaMissense: likely benign (0.2727); Absent from gnomAD v4.1.

How common is TPH1 p.Arg191Ser (c.573A>C) in the general population?

TPH1 p.Arg191Ser (c.573A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TPH1 p.Arg191Ser (c.573A>C)?

AlphaMissense predicts likely benign (score 0.2727) — an in-silico prediction, not a clinical call.

TPH1 p.Arg191Ser

c.573A>C · rs2493993868 · VCV2550767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2727 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2727	likely benign
REVEL	0.725	pathogenic-leaning
SaProt	LLR -7.81	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.99 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.88	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 20 kb · p 0.11 · regional, not allelic
Overall
CADD	23.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TPH1
Protein: p.Arg191Ser
Coding: c.573A>C
MANE Select: NM_004179
dbSNP: rs2493993868
Type: single nucleotide variant
Location: chr11:18029259 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.96 · 21 PDB
Residue 191: an α-helix

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.Arg224Cys Uncertain significance ★ ⚠ same type
TPH1 p.Arg224His Uncertain significance ★ ⚠ same type
TPH1 p.Arg230Cys 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-arg191ser (accessed [today's date]).

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