Is TTI2 p.Val387Asp (c.1160T>A) pathogenic?

TTI2 p.Val387Asp (c.1160T>A) is classified Uncertain significance in TTI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.9041); Very rare (popmax 6.2e-05%).

How common is TTI2 p.Val387Asp (c.1160T>A) in the general population?

TTI2 p.Val387Asp (c.1160T>A) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about TTI2 p.Val387Asp (c.1160T>A)?

AlphaMissense predicts likely pathogenic (score 0.9041) — an in-silico prediction, not a clinical call.

TTI2 p.Val387Asp

c.1160T>A · VCV3343465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9041 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9041	likely pathogenic · top 2% in TTI2
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -12.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	28.8	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 6.2e-05%

Overall 6.2e-05% 1/1,614,012 alleles · very rare exomes 1/1,461,886 · genomes 0/152,126 · joint denominator

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.Val387Asp
Coding: c.1160T>A
MANE Select: NM_001102401
Type: single nucleotide variant
Location: chr8:33503528 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.85 · 2 PDB

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

Similar variants

TTI2 p.Arg334Gln Uncertain significance ★★ ⚠ same type
TTI2 p.Arg355His Uncertain significance ★★ ⚠ same type
TTI2 p.Arg379Trp Uncertain significance ★★ ⚠ same type
TTI2 p.Gly190Val Uncertain significance ★★ ⚠ same type
TTI2 p.Pro149Leu Uncertain significance ★★ ⚠ same type
TTI2 p.Thr232Ile Uncertain significance ★★ ⚠ same type
TTI2 p.Thr237Ala Uncertain significance ★★ ⚠ same type
TTI2 c.-99-31C>T 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/tti2-p-val387asp (accessed [today's date]).

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