Is TTI1 p.Glu76fs (c.221_224dup) pathogenic?

TTI1 p.Glu76fs (c.221224dup) is classified Likely pathogenic in TTI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). Associated with neurodevelopmental disorder with microcephaly and movement abnormalities.

What condition is associated with TTI1 p.Glu76fs (c.221_224dup)?

TTI1 p.Glu76fs (c.221_224dup) is associated with neurodevelopmental disorder with microcephaly and movement abnormalities (ClinVar).

TTI1 p.Glu76fs

c.221_224dup · VCV4850461

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

neurodevelopmental disorder with microcephaly and movement abnormalities

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.085	GERP 0.41, phastCons 0.9

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: TTI1
Protein: p.Glu76fs
Coding: c.221_224dup
MANE Select: NM_001303457
Type: Duplication
Location: chr20:38013592 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38 · 3 PDB
Residue 76: 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

neurodevelopmental disorder with microcephaly and movement abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TTI1 p.Leu210fs Uncertain significance same condition
TTI1 p.Ile634Thr Uncertain significance ★★ ⚠ same condition
TTI1 p.Ala671Thr Likely pathogenic ★ same condition
TTI1 p.Asp921Asn Likely pathogenic ★ ⚠ same condition
TTI1 p.Arg519Trp Uncertain significance ★ same condition
TTI1 p.Leu181Pro Uncertain significance ★ ⚠ same condition
TTI1 p.Leu410Pro Uncertain significance ★ ⚠ same condition
TTI1 p.Thr22Arg 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-glu76fs (accessed [today's date]).

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