Is TTI2 p.Arg355Cys (c.1063C>T) pathogenic?

TTI2 p.Arg355Cys (c.1063C>T) is classified Conflicting classifications of pathogenicity in TTI2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.188); Rare (popmax 0.546%, nfe).

How common is TTI2 p.Arg355Cys (c.1063C>T) in the general population?

TTI2 p.Arg355Cys (c.1063C>T) is rare (popmax 0.546%, nfe) (gnomAD).

What do computational predictors say about TTI2 p.Arg355Cys (c.1063C>T)?

AlphaMissense predicts likely benign (score 0.188) — an in-silico prediction, not a clinical call.

TTI2 p.Arg355Cys

c.1063C>T · rs138108276 · VCV437081

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.188 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.546%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.188	likely benign
REVEL	0.519	indeterminate
SaProt	LLR -7.34	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	32.0	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 0.546% European (non-Finnish) · 6,440/1,180,002 alleles

Filtering AF 0.535% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.53%

Overall 0.459% 7,411/1,614,010 alleles · rare exomes 6,846/1,461,780 · genomes 565/152,230 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	3.84%	26
Finnishnot grpmax-eligible	0.809%	124
European (non-Finnish)grpmax	0.546%	183
Remaining individualsnot grpmax-eligible	0.379%	264
South Asian	0.0845%	1,183
Admixed American	0.0733%	1,363
African / African-American	0.064%	1,563
East Asian	0.0201%	4,986
Middle Eastern	0.0166%	6,014
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg355Cys
Coding: c.1063C>T
MANE Select: NM_001102401
dbSNP: rs138108276
Type: single nucleotide variant
Location: chr8:33503800 (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

Similar variants

TTI2 p.Arg355His Uncertain significance ★★ ⚠ same residue
TTI2 p.Arg334Gln Uncertain significance ★★ ⚠ same type
TTI2 p.Arg379Trp Uncertain significance ★★ ⚠ same type
TTI2 p.Gly190Val Uncertain significance ★★ ⚠ same type
TTI2 p.Pro149Leu Uncertain significance ★★ ⚠ same type
TTI2 p.Thr232Ile Uncertain significance ★★ ⚠ same type
TTI2 p.Thr237Ala Uncertain significance ★★ ⚠ same type
TTI2 c.-99-31C>T Benign ★★ same type

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-arg355cys (accessed [today's date]).

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