Is TTI1 p.Leu592Phe (c.1774C>T) pathogenic?

TTI1 p.Leu592Phe (c.1774C>T) is classified Uncertain significance in TTI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-28). AlphaMissense: likely benign (0.0694); Ultra-rare (popmax 0.0133%, amr); Associated with Inborn genetic diseases.

What condition is associated with TTI1 p.Leu592Phe (c.1774C>T)?

TTI1 p.Leu592Phe (c.1774C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TTI1 p.Leu592Phe (c.1774C>T) in the general population?

TTI1 p.Leu592Phe (c.1774C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about TTI1 p.Leu592Phe (c.1774C>T)?

AlphaMissense predicts likely benign (score 0.0694) — an in-silico prediction, not a clinical call.

TTI1 p.Leu592Phe

c.1774C>T · rs768880719 · VCV2403955

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0694 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0694	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -7.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 30 kb · p 0.00063 · regional, not allelic
Overall
CADD	6.832	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 0.0133% Admixed American · 8/60,006 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.000558% 9/1,614,098 alleles · ultra-rare exomes 8/1,461,892 · genomes 1/152,206 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,501
European (non-Finnish)	8.47e-05%	1,180,054

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.Leu592Phe
Coding: c.1774C>T
MANE Select: NM_001303457
dbSNP: rs768880719
Type: single nucleotide variant
Location: chr20:38012043 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38 · 3 PDB
Residue 592: 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

Similar variants

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
TTI1 p.Ile862Val 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-leu592phe (accessed [today's date]).

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