Is TTI1 p.Phe225Leu (c.673T>C) pathogenic?

TTI1 p.Phe225Leu (c.673T>C) is classified Uncertain significance in TTI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-07). AlphaMissense: ambiguous (0.4624); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TTI1 p.Phe225Leu (c.673T>C)?

TTI1 p.Phe225Leu (c.673T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TTI1 p.Phe225Leu (c.673T>C) in the general population?

TTI1 p.Phe225Leu (c.673T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TTI1 p.Phe225Leu (c.673T>C)?

AlphaMissense predicts ambiguous (score 0.4624) — an in-silico prediction, not a clinical call.

TTI1 p.Phe225Leu

c.673T>C · rs1332031521 · VCV2311010

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4624 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4624	ambiguous
REVEL	0.13	moderately benign-leaning
SaProt	LLR -2.92	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.4	GERP 2.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 30 kb · p 0.00063 · regional, not allelic
Overall
CADD	18.56	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TTI1
Protein: p.Phe225Leu
Coding: c.673T>C
MANE Select: NM_001303457
dbSNP: rs1332031521
Type: single nucleotide variant
Location: chr20:38013144 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38 · 3 PDB
Residue 225: 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

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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-phe225leu (accessed [today's date]).

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