Is TTI2 p.Leu119Pro (c.356T>C) pathogenic?

TTI2 p.Leu119Pro (c.356T>C) is classified Uncertain significance in TTI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). AlphaMissense: ambiguous (0.5378); Very rare (popmax 0.000678%, nfe); Associated with severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome.

How common is TTI2 p.Leu119Pro (c.356T>C) in the general population?

TTI2 p.Leu119Pro (c.356T>C) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about TTI2 p.Leu119Pro (c.356T>C)?

AlphaMissense predicts ambiguous (score 0.5378) — an in-silico prediction, not a clinical call.

TTI2 p.Leu119Pro

Q: What condition is associated with TTI2 p.Leu119Pro (c.356T>C)?

TTI2 p.Leu119Pro (c.356T>C) is associated with severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome (ClinVar).

c.356T>C · rs779111618 · VCV3068291

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5378 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.5378	ambiguous
REVEL	0.343	indeterminate
SaProt	LLR -15.26	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 0.95
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,180,040 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,614,086 alleles · very rare exomes 7/1,461,884 · genomes 1/152,202 · 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.Leu119Pro
Coding: c.356T>C
MANE Select: NM_001102401
dbSNP: rs779111618
Type: single nucleotide variant
Location: chr8:33512258 (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

severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TTI2 p.Arg334Gln Uncertain significance ★★ ⚠ same condition
TTI2 p.Arg355His Uncertain significance ★★ ⚠ same condition
TTI2 p.Thr232Ile Uncertain significance ★★ ⚠ same condition
TTI2 c.-99-31C>T Benign ★★ same condition
TTI2 p.Asn46= Benign ★★ same condition
TTI2 p.Glu63Gly Benign ★★ same condition
TTI2 c.1115+1G>A Likely pathogenic ★ same condition
TTI2 c.1115+2T>C Likely pathogenic ★ 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-leu119pro (accessed [today's date]).

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