Is TTI2 p.Pro367Leu (c.1100C>T) pathogenic?

TTI2 p.Pro367Leu (c.1100C>T) is classified Pathogenic in TTI2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-05). AlphaMissense: likely benign (0.2511); Very rare (popmax 0.00549%, sas); Associated with Inborn genetic diseases.

What condition is associated with TTI2 p.Pro367Leu (c.1100C>T)?

TTI2 p.Pro367Leu (c.1100C>T) is associated with Inborn genetic diseases, severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome (ClinVar).

How common is TTI2 p.Pro367Leu (c.1100C>T) in the general population?

TTI2 p.Pro367Leu (c.1100C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about TTI2 p.Pro367Leu (c.1100C>T)?

AlphaMissense predicts likely benign (score 0.2511) — an in-silico prediction, not a clinical call.

TTI2 p.Pro367Leu

c.1100C>T · rs398122366 · VCV88867

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2511 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2511	likely benign ⚠ discordant with ClinVar
REVEL	0.621	indeterminate
SaProt	LLR -12.89	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	24.0	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 0.00549% South Asian · 5/91,040 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000992% 16/1,613,586 alleles · very rare exomes 14/1,461,478 · genomes 2/152,108 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,208
East Asian	0.00445%	22,447
European (non-Finnish)	0.000763%	131,108

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.Pro367Leu
Coding: c.1100C>T
MANE Select: NM_001102401
dbSNP: rs398122366
Type: single nucleotide variant
Location: chr8:33503763 (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.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.Thr232Ile 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-pro367leu (accessed [today's date]).

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