Is TDO2 p.Ser266Phe (c.797C>T) pathogenic?

TDO2 p.Ser266Phe (c.797C>T) is classified Uncertain significance in TDO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.2971); Ultra-rare (popmax 0.0566%, afr).

How common is TDO2 p.Ser266Phe (c.797C>T) in the general population?

TDO2 p.Ser266Phe (c.797C>T) is ultra-rare (popmax 0.0566%, afr) (gnomAD).

What do computational predictors say about TDO2 p.Ser266Phe (c.797C>T)?

AlphaMissense predicts likely benign (score 0.2971) — an in-silico prediction, not a clinical call.

TDO2 p.Ser266Phe

c.797C>T · VCV4181839

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2971 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0566%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2971	likely benign
REVEL	0.738	pathogenic-leaning
SaProt	LLR -10.23	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 0.93, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 16 kb · p 0.26 · regional, not allelic
Overall
CADD	24.7	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 0.0566% African / African-American · 42/74,262 alleles

Filtering AF 0.0429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0382%

Overall 0.00381% 61/1,602,902 alleles · ultra-rare exomes 29/1,450,784 · genomes 32/152,118 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0566%	1,768
Admixed American	0.023%	4,344
Remaining individualsnot grpmax-eligible	0.00967%	10,343

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: TDO2
Protein: p.Ser266Phe
Coding: c.797C>T
MANE Select: NM_005651
Type: single nucleotide variant
Location: chr4:155914393 (GRCh38)
Gene constraint: LOEUF 1.104 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.63 · 22 PDB
Residue 266: an α-helix

Full TDO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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
TPH2 p.Pro180= 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/tdo2-p-ser266phe (accessed [today's date]).

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