Is TPH2 p.Arg88Cys (c.262C>T) pathogenic?

TPH2 p.Arg88Cys (c.262C>T) is classified Uncertain significance in TPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.1461); Very rare (popmax 0.00223%, eas); Associated with Tryptophan 5-monooxygenase deficiency.

What condition is associated with TPH2 p.Arg88Cys (c.262C>T)?

TPH2 p.Arg88Cys (c.262C>T) is associated with Tryptophan 5-monooxygenase deficiency (ClinVar).

How common is TPH2 p.Arg88Cys (c.262C>T) in the general population?

TPH2 p.Arg88Cys (c.262C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about TPH2 p.Arg88Cys (c.262C>T)?

AlphaMissense predicts likely benign (score 0.1461) — an in-silico prediction, not a clinical call.

TPH2 p.Arg88Cys

c.262C>T · rs779979959 · VCV310380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1461 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Tryptophan 5-monooxygenase deficiency

Computational evidence

Protein change
AlphaMissense	0.1461	likely benign
REVEL	0.552	indeterminate
SaProt	LLR -8.26	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 6	GERP 1.9, phastCons 1
Overall
CADD	24.7	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 0.00223% East Asian · 1/44,866 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,456 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,866
European (non-Finnish)	0.00017%	589,863

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.Arg88Cys
Coding: c.262C>T
MANE Select: NM_005651 · reported on NM_173353
dbSNP: rs779979959
Type: single nucleotide variant
Location: chr12:71944300 (GRCh38)
Structure: AlphaFold pLDDT 90.63 · 22 PDB
Residue 88: an α-helix

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

Disease context

Tryptophan 5-monooxygenase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TPH2 c.-52A>G Benign ★★ same condition
TPH2 c.*149G>A Likely benign ★★ same condition
TPH2 c.*479G>A Benign ★★ same condition
TPH2 p.Ala375= Benign ★★ same condition
TPH2 p.Leu36Val Benign/Likely benign ★★ same condition
TPH2 p.Pro180= Benign/Likely benign ★★ same condition
TPH2 p.Pro312= Benign ★★ same condition
TPH2 c.1164+7A>G Uncertain significance ★ same condition

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-arg88cys (accessed [today's date]).

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