Is TTI2 p.Arg334Gln (c.1001G>A) pathogenic?

TTI2 p.Arg334Gln (c.1001G>A) is classified Uncertain significance in TTI2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-05). AlphaMissense: likely benign (0.0988); Ultra-rare (popmax 0.0627%, afr); Associated with Inborn genetic diseases.

What condition is associated with TTI2 p.Arg334Gln (c.1001G>A)?

TTI2 p.Arg334Gln (c.1001G>A) is associated with Inborn genetic diseases, severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome (ClinVar).

How common is TTI2 p.Arg334Gln (c.1001G>A) in the general population?

TTI2 p.Arg334Gln (c.1001G>A) is ultra-rare (popmax 0.0627%, afr) (gnomAD).

What do computational predictors say about TTI2 p.Arg334Gln (c.1001G>A)?

AlphaMissense predicts likely benign (score 0.0988) — an in-silico prediction, not a clinical call.

TTI2 p.Arg334Gln

c.1001G>A · rs143370889 · VCV1029081

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0988 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0627%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0988	likely benign
REVEL	0.379	indeterminate
SaProt	LLR -7.15	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0627% African / African-American · 47/75,016 alleles

Filtering AF 0.0483% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0433%

Overall 0.00576% 93/1,614,072 alleles · ultra-rare exomes 56/1,461,868 · genomes 37/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0627%	1,596
Admixed American	0.0317%	3,158
South Asian	0.011%	9,107
Remaining individualsnot grpmax-eligible	0.0064%	15,625
Finnishnot grpmax-eligible	0.00156%	64,010
European (non-Finnish)	0.00102%	98,336

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.Arg334Gln
Coding: c.1001G>A
MANE Select: NM_001102401
dbSNP: rs143370889
Type: single nucleotide variant
Location: chr8:33503862 (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.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
TTI2 p.Asn46= 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-arg334gln (accessed [today's date]).

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