Is TTI2 p.Leu180Pro (c.539T>C) pathogenic?

TTI2 p.Leu180Pro (c.539T>C) is classified Pathogenic in TTI2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-06-21). AlphaMissense: likely pathogenic (0.6932); Very rare (popmax 0.00161%, nfe); Associated with severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome.

How common is TTI2 p.Leu180Pro (c.539T>C) in the general population?

TTI2 p.Leu180Pro (c.539T>C) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about TTI2 p.Leu180Pro (c.539T>C)?

AlphaMissense predicts likely pathogenic (score 0.6932) — an in-silico prediction, not a clinical call.

TTI2 p.Leu180Pro

Q: What condition is associated with TTI2 p.Leu180Pro (c.539T>C)?

TTI2 p.Leu180Pro (c.539T>C) is associated with severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome (ClinVar).

c.539T>C · rs765235179 · VCV2506446

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.6932	likely pathogenic ✓ concordant with ClinVar · top 10% in TTI2
REVEL	0.536	indeterminate
SaProt	LLR -14.75	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	28.5	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 0.00161% European (non-Finnish) · 19/1,180,018 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00124% 20/1,613,970 alleles · very rare exomes 17/1,461,890 · genomes 3/152,080 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,106
African / African-American	0.00134%	74,884

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.Leu180Pro
Coding: c.539T>C
MANE Select: NM_001102401
dbSNP: rs765235179
Type: single nucleotide variant
Location: chr8:33512075 (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-leu180pro (accessed [today's date]).

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