Is TTI2 p.Leu429Pro (c.1286T>C) pathogenic?

TTI2 p.Leu429Pro (c.1286T>C) is classified Uncertain significance in TTI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). AlphaMissense: likely pathogenic (0.8648); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with TTI2 p.Leu429Pro (c.1286T>C)?

TTI2 p.Leu429Pro (c.1286T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TTI2 p.Leu429Pro (c.1286T>C) in the general population?

TTI2 p.Leu429Pro (c.1286T>C) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about TTI2 p.Leu429Pro (c.1286T>C)?

AlphaMissense predicts likely pathogenic (score 0.8648) — an in-silico prediction, not a clinical call.

TTI2 p.Leu429Pro

c.1286T>C · VCV4193426

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8648 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.8648	likely pathogenic
REVEL	0.702	pathogenic-leaning
SaProt	LLR -11.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	25.0	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 0.005% Admixed American · 3/60,002 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00118% 19/1,614,046 alleles · very rare exomes 18/1,461,852 · genomes 1/152,194 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,001
European (non-Finnish)	0.00136%	73,752

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: TTI2
Protein: p.Leu429Pro
Coding: c.1286T>C
MANE Select: NM_001102401
Type: single nucleotide variant
Location: chr8:33500464 (GRCh38)

Full TTI2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/tti2-p-leu429pro (accessed [today's date]).

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