Is TTI2 p.Thr232Ile (c.695C>T) pathogenic?

TTI2 p.Thr232Ile (c.695C>T) is classified Uncertain significance in TTI2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.28); Very rare (popmax 0.00529%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TTI2 p.Thr232Ile (c.695C>T)?

TTI2 p.Thr232Ile (c.695C>T) is associated with Inborn genetic diseases, severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome (ClinVar).

How common is TTI2 p.Thr232Ile (c.695C>T) in the general population?

TTI2 p.Thr232Ile (c.695C>T) is very rare (popmax 0.00529%, nfe) (gnomAD).

What do computational predictors say about TTI2 p.Thr232Ile (c.695C>T)?

AlphaMissense predicts likely benign (score 0.28) — an in-silico prediction, not a clinical call.

TTI2 p.Thr232Ile

c.695C>T · rs369757546 · VCV437083

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.28 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00529%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.28	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -8.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 5.8	GERP 0.74, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	20.6	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 0.00529% European (non-Finnish) · 62/1,172,952 alleles

Filtering AF 0.00421% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00382%

Overall 0.00406% 65/1,600,962 alleles · very rare exomes 56/1,450,910 · genomes 9/150,052 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00529%	18,919
African / African-American	0.00271%	36,912
Admixed American	0.00169%	59,210

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.Thr232Ile
Coding: c.695C>T
MANE Select: NM_001102401
dbSNP: rs369757546
Type: single nucleotide variant
Location: chr8:33509885 (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

Disease context

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

Also linked: severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome

Similar variants

TTI2 p.Thr232Ala Uncertain significance ★ ⚠ same residue
TTI2 p.Arg334Gln Uncertain significance ★★ ⚠ same condition
TTI2 p.Arg355His Uncertain significance ★★ ⚠ same condition
TTI2 p.Arg379Trp Uncertain significance ★★ ⚠ same condition
TTI2 p.Gly190Val Uncertain significance ★★ ⚠ same condition
TTI2 p.Pro149Leu Uncertain significance ★★ ⚠ same condition
TTI2 p.Thr237Ala Uncertain significance ★★ ⚠ same condition
TTI2 c.-99-31C>T Benign ★★ 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/tti2-p-thr232ile (accessed [today's date]).

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