Is TTI1 p.Val888Met (c.2662G>A) pathogenic?

TTI1 p.Val888Met (c.2662G>A) is classified Uncertain significance in TTI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: likely benign (0.213); Ultra-rare (popmax 0.0301%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TTI1 p.Val888Met (c.2662G>A)?

TTI1 p.Val888Met (c.2662G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TTI1 p.Val888Met (c.2662G>A) in the general population?

TTI1 p.Val888Met (c.2662G>A) is ultra-rare (popmax 0.0301%, nfe) (gnomAD).

What do computational predictors say about TTI1 p.Val888Met (c.2662G>A)?

AlphaMissense predicts likely benign (score 0.213) — an in-silico prediction, not a clinical call.

TTI1 p.Val888Met

c.2662G>A · rs148752956 · VCV2266044

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.213 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0301%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.213	likely benign
REVEL	0.345	indeterminate
SaProt	LLR -10.40	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 30 kb · p 0.00063 · regional, not allelic
Overall
CADD	25.5	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 0.0301% European (non-Finnish) · 325/1,079,442 alleles

Filtering AF 0.0274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0264%

Overall 0.0243% 346/1,422,644 alleles · ultra-rare exomes 323/1,270,424 · genomes 23/152,220 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0301%	3,321
Remaining individualsnot grpmax-eligible	0.03%	3,331
African / African-American	0.00733%	13,634

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.Val888Met
Coding: c.2662G>A
MANE Select: NM_001303457
dbSNP: rs148752956
Type: single nucleotide variant
Location: chr20:37999319 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38 · 3 PDB
Residue 888: 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-val888met (accessed [today's date]).

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