Is TTI2 p.Lys451Ter (c.1350dup) pathogenic?

TTI2 p.Lys451Ter (c.1350dup) is classified Conflicting classifications of pathogenicity in TTI2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-01-22). Ultra-rare (popmax 0.0454%, afr); Associated with severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome.

How common is TTI2 p.Lys451Ter (c.1350dup) in the general population?

TTI2 p.Lys451Ter (c.1350dup) is ultra-rare (popmax 0.0454%, afr) (gnomAD).

TTI2 p.Lys451Ter

Q: What condition is associated with TTI2 p.Lys451Ter (c.1350dup)?

TTI2 p.Lys451Ter (c.1350dup) is associated with severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome (ClinVar).

c.1350dup · rs758541435 · VCV593064

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0454%, afr)

Conditions

severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome

⚠ 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
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.1	GERP 1.6, phastCons 1
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0454% African / African-American · 34/74,908 alleles

Filtering AF 0.0334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0292%

Overall 0.00242% 39/1,614,062 alleles · ultra-rare exomes 14/1,461,874 · genomes 25/152,188 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0454%	2,203
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	8.47e-05%	1,180,032

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.Lys451Ter
Coding: c.1350dup
MANE Select: NM_001102401
dbSNP: rs758541435
Type: Duplication
Location: chr8:33500399 (GRCh38)

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

Disease context

severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome — 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-lys451ter (accessed [today's date]).

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