Is TTI1 p.Phe508Leu (c.1522T>C) pathogenic?

TTI1 p.Phe508Leu (c.1522T>C) is classified Uncertain significance in TTI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: likely pathogenic (0.7341); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with TTI1 p.Phe508Leu (c.1522T>C)?

TTI1 p.Phe508Leu (c.1522T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TTI1 p.Phe508Leu (c.1522T>C) in the general population?

TTI1 p.Phe508Leu (c.1522T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about TTI1 p.Phe508Leu (c.1522T>C)?

AlphaMissense predicts likely pathogenic (score 0.7341) — an in-silico prediction, not a clinical call.

TTI1 p.Phe508Leu

c.1522T>C · VCV3812039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7341 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7341	likely pathogenic · top 10% in TTI1
REVEL	0.208	benign-leaning
SaProt	LLR -7.51	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 30 kb · p 0.00063 · regional, not allelic
Overall
CADD	23.2	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 0.00333% Admixed American · 2/60,026 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000681% 11/1,614,210 alleles · very rare exomes 11/1,461,888 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,013
Remaining individualsnot grpmax-eligible	0.0032%	31,256
European (non-Finnish)	0.000593%	168,577

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.Phe508Leu
Coding: c.1522T>C
MANE Select: NM_001303457
Type: single nucleotide variant
Location: chr20:38012295 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38 · 3 PDB
Residue 508: 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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TTI1 p.His229Tyr Uncertain significance ★★ ⚠ same condition
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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-phe508leu (accessed [today's date]).

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