Is TTI1 p.Arg15Cys (c.43C>T) pathogenic?

TTI1 p.Arg15Cys (c.43C>T) is classified Uncertain significance in TTI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-25). AlphaMissense: likely pathogenic (0.6486); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with TTI1 p.Arg15Cys (c.43C>T)?

TTI1 p.Arg15Cys (c.43C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TTI1 p.Arg15Cys (c.43C>T) in the general population?

TTI1 p.Arg15Cys (c.43C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about TTI1 p.Arg15Cys (c.43C>T)?

AlphaMissense predicts likely pathogenic (score 0.6486) — an in-silico prediction, not a clinical call.

TTI1 p.Arg15Cys

c.43C>T · VCV3812043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6486 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6486	likely pathogenic
REVEL	0.859	moderately pathogenic-leaning
SaProt	LLR -12.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 30 kb · p 0.00063 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.004% African / African-American · 3/74,924 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000929% 15/1,613,882 alleles · very rare exomes 13/1,461,684 · genomes 2/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,975
Admixed American	0.00333%	30,003
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.000678%	147,504

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: TTI1
Protein: p.Arg15Cys
Coding: c.43C>T
MANE Select: NM_001303457
Type: single nucleotide variant
Location: chr20:38013774 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38 · 3 PDB

Full TTI1 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

TTI1 p.Arg15His Uncertain significance ★ ⚠ same residue
TTI1 p.Ala806Thr Uncertain significance ★★ ⚠ same condition
TTI1 p.Arg519Gln Uncertain significance ★★ ⚠ same condition
TTI1 p.Arg724Gly Uncertain significance ★★ ⚠ same condition
TTI1 p.Arg869Cys Uncertain significance ★★ same condition
TTI1 p.Cys86Tyr Uncertain significance ★★ ⚠ same condition
TTI1 p.His229Tyr Uncertain significance ★★ ⚠ same condition
TTI1 p.His513Tyr Uncertain significance ★★ ⚠ 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/tti1-p-arg15cys (accessed [today's date]).

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