Is TTI1 p.Thr596Met (c.1787C>T) pathogenic?

TTI1 p.Thr596Met (c.1787C>T) is classified Uncertain significance in TTI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). AlphaMissense: likely benign (0.0809); Rare (popmax 0.385%, afr); Associated with Inborn genetic diseases.

What condition is associated with TTI1 p.Thr596Met (c.1787C>T)?

TTI1 p.Thr596Met (c.1787C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TTI1 p.Thr596Met (c.1787C>T) in the general population?

TTI1 p.Thr596Met (c.1787C>T) is rare (popmax 0.385%, afr) (gnomAD).

What do computational predictors say about TTI1 p.Thr596Met (c.1787C>T)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

TTI1 p.Thr596Met

c.1787C>T · VCV3463546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.385%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.5	GERP 0.25, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 30 kb · p 0.00063 · regional, not allelic
Overall
CADD	14.87	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 0.385% African / African-American · 289/75,054 alleles

Filtering AF 0.348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.334%

Overall 0.0206% 332/1,614,220 alleles · rare exomes 159/1,461,892 · genomes 173/152,328 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.385%	260
Admixed American	0.0233%	4,288
Remaining individualsnot grpmax-eligible	0.0224%	4,465
Middle Eastern	0.0165%	6,062
East Asian	0.00223%	44,880
South Asian	0.0022%	45,545
European (non-Finnish)	0.000932%	107,276

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.Thr596Met
Coding: c.1787C>T
MANE Select: NM_001303457
Type: single nucleotide variant
Location: chr20:38012030 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38 · 3 PDB
Residue 596: a UniProt-annotated variant site (in nedmim; likely pathogenic)

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

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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-thr596met (accessed [today's date]).

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