Is TTI2 p.Phe229= (c.687C>T) pathogenic?

TTI2 p.Phe229= (c.687C>T) is classified Likely benign in TTI2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-04-08). Very rare (popmax 0.00044%, nfe); Associated with TTI2-related disorder.

What condition is associated with TTI2 p.Phe229= (c.687C>T)?

TTI2 p.Phe229= (c.687C>T) is associated with TTI2-related disorder (ClinVar).

How common is TTI2 p.Phe229= (c.687C>T) in the general population?

TTI2 p.Phe229= (c.687C>T) is very rare (popmax 0.00044%, nfe) (gnomAD).

TTI2 p.Phe229=

c.687C>T · rs1038077253 · VCV3046396

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00044%, nfe)

Conditions

TTI2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.3	GERP -1.4, phastCons 1
Overall
CADD	11.76	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00044% European (non-Finnish) · 5/1,135,760 alleles

Filtering AF 0.000129% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.4e-05%

Overall 0.00039% 6/1,538,086 alleles · very rare exomes 5/1,393,822 · genomes 1/144,264 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00173%	57,644
European (non-Finnish)grpmax	0.00044%	227,152

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: TTI2
Protein: p.Phe229=
Coding: c.687C>T
MANE Select: NM_001102401
dbSNP: rs1038077253
Type: single nucleotide variant
Location: chr8:33509893 (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

TTI2-related disorder

Similar variants

TTI2 p.Phe229Leu Uncertain significance ★ ⚠ same residue
TTI2 p.Asp317Val Pathogenic ★ same condition
TTI2 p.Leu266= Likely benign same condition
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

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-phe229 (accessed [today's date]).

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