Is TTI1 p.Leu997Pro (c.2990T>C) pathogenic?

TTI1 p.Leu997Pro (c.2990T>C) is classified Likely pathogenic in TTI1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-12-04). AlphaMissense: likely pathogenic (0.8979); Absent from gnomAD v4.1.

How common is TTI1 p.Leu997Pro (c.2990T>C) in the general population?

TTI1 p.Leu997Pro (c.2990T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TTI1 p.Leu997Pro (c.2990T>C)?

AlphaMissense predicts likely pathogenic (score 0.8979) — an in-silico prediction, not a clinical call.

TTI1 p.Leu997Pro

c.2990T>C · rs2515417992 · VCV2664648

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8979 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8979	likely pathogenic ✓ concordant with ClinVar · top 4% in TTI1
REVEL	0.601	indeterminate
SaProt	LLR -15.02	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 30 kb · p 0.00063 · regional, not allelic
Overall
CADD	26.5	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

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.Leu997Pro
Coding: c.2990T>C
MANE Select: NM_001303457
dbSNP: rs2515417992
Type: single nucleotide variant
Location: chr20:37996757 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38 · 3 PDB
Residue 997: a UniProt-annotated variant site (in nedmim; likely pathogenic)

Full TTI1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TTI1 p.Ala806Thr Uncertain significance ★★ ⚠ same type
TTI1 p.Arg519Gln Uncertain significance ★★ ⚠ same type
TTI1 p.Arg724Gly Uncertain significance ★★ ⚠ same type
TTI1 p.Arg869Cys Uncertain significance ★★ same type
TTI1 p.Cys86Tyr Uncertain significance ★★ ⚠ same type
TTI1 p.His229Tyr Uncertain significance ★★ ⚠ same type
TTI1 p.His513Tyr Uncertain significance ★★ ⚠ same type
TTI1 p.Ile634Thr Uncertain significance ★★ ⚠ same type

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-leu997pro (accessed [today's date]).

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