Is TTI2 p.Arg359Cys (c.1075C>T) pathogenic?

TTI2 p.Arg359Cys (c.1075C>T) is classified Uncertain significance in TTI2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-31). AlphaMissense: ambiguous (0.4732); Very rare (popmax 0.00229%, nfe); Associated with severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome.

How common is TTI2 p.Arg359Cys (c.1075C>T) in the general population?

TTI2 p.Arg359Cys (c.1075C>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about TTI2 p.Arg359Cys (c.1075C>T)?

AlphaMissense predicts ambiguous (score 0.4732) — an in-silico prediction, not a clinical call.

TTI2 p.Arg359Cys

Q: What condition is associated with TTI2 p.Arg359Cys (c.1075C>T)?

TTI2 p.Arg359Cys (c.1075C>T) is associated with severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome (ClinVar).

c.1075C>T · rs770858092 · VCV2506444

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.4732	ambiguous
REVEL	0.804	moderately pathogenic-leaning
SaProt	LLR -10.14	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	33.0	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 0.00229% European (non-Finnish) · 27/1,180,002 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.0018% 29/1,613,862 alleles · very rare exomes 27/1,461,720 · genomes 2/152,142 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,704
African / African-American	0.00133%	74,922
South Asian	0.0011%	91,066

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.Arg359Cys
Coding: c.1075C>T
MANE Select: NM_001102401
dbSNP: rs770858092
Type: single nucleotide variant
Location: chr8:33503788 (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.Arg359His Uncertain significance ★ ⚠ same residue
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

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-arg359cys (accessed [today's date]).

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