Is TDO2 p.Pro307Ser (c.919C>T) pathogenic?

TDO2 p.Pro307Ser (c.919C>T) is classified Uncertain significance in TDO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-22). AlphaMissense: likely pathogenic (0.7133); Very rare (popmax 0.000509%, nfe).

How common is TDO2 p.Pro307Ser (c.919C>T) in the general population?

TDO2 p.Pro307Ser (c.919C>T) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about TDO2 p.Pro307Ser (c.919C>T)?

AlphaMissense predicts likely pathogenic (score 0.7133) — an in-silico prediction, not a clinical call.

TDO2 p.Pro307Ser

c.919C>T · rs749290880 · VCV2527976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7133	likely pathogenic
REVEL	0.578	indeterminate
SaProt	LLR -9.34	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 16 kb · p 0.26 · regional, not allelic
Overall
CADD	24.6	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 0.000509% European (non-Finnish) · 6/1,178,782 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000497% 8/1,610,722 alleles · very rare exomes 8/1,458,514 · genomes 0/152,208 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,160
European (non-Finnish)grpmax	0.000509%	196,464

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro307Ser
Coding: c.919C>T
MANE Select: NM_005651
dbSNP: rs749290880
Type: single nucleotide variant
Location: chr4:155917417 (GRCh38)
Gene constraint: LOEUF 1.104 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.63 · 22 PDB
Residue 307: 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-pro307ser (accessed [today's date]).

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