Is TTI2 p.Arg379Trp (c.1135C>T) pathogenic?

TTI2 p.Arg379Trp (c.1135C>T) is classified Uncertain significance in TTI2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-18). AlphaMissense: likely benign (0.2406); Ultra-rare (popmax 0.0351%, sas); Associated with Inborn genetic diseases.

What condition is associated with TTI2 p.Arg379Trp (c.1135C>T)?

TTI2 p.Arg379Trp (c.1135C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TTI2 p.Arg379Trp (c.1135C>T) in the general population?

TTI2 p.Arg379Trp (c.1135C>T) is ultra-rare (popmax 0.0351%, sas) (gnomAD).

What do computational predictors say about TTI2 p.Arg379Trp (c.1135C>T)?

AlphaMissense predicts likely benign (score 0.2406) — an in-silico prediction, not a clinical call.

TTI2 p.Arg379Trp

c.1135C>T · rs140977711 · VCV1337372

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2406 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0351%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2406	likely benign
REVEL	0.556	indeterminate
SaProt	LLR -11.18	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 4.4	GERP -0.072, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	29.0	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 0.0351% South Asian · 32/91,064 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.0141% 228/1,613,944 alleles · ultra-rare exomes 214/1,461,800 · genomes 14/152,144 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0351%	2,846
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.0153%	6,519
Remaining individualsnot grpmax-eligible	0.008%	12,502
African / African-American	0.00667%	15,002
East Asian	0.00446%	22,433
Admixed American	0.00333%	29,993

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.Arg379Trp
Coding: c.1135C>T
MANE Select: NM_001102401
dbSNP: rs140977711
Type: single nucleotide variant
Location: chr8:33503553 (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

Similar variants

TTI2 p.Arg379Gln Uncertain significance ★ ⚠ same residue
TTI2 p.Arg334Gln Uncertain significance ★★ ⚠ same condition
TTI2 p.Arg355His 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 p.Pro367Leu 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-arg379trp (accessed [today's date]).

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