Is TTI1 p.Thr22Arg (c.65C>G) pathogenic?

TTI1 p.Thr22Arg (c.65C>G) is classified Uncertain significance in TTI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). AlphaMissense: likely pathogenic (0.7386); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with microcephaly and movement abnormalities.

What condition is associated with TTI1 p.Thr22Arg (c.65C>G)?

TTI1 p.Thr22Arg (c.65C>G) is associated with neurodevelopmental disorder with microcephaly and movement abnormalities (ClinVar).

How common is TTI1 p.Thr22Arg (c.65C>G) in the general population?

TTI1 p.Thr22Arg (c.65C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TTI1 p.Thr22Arg (c.65C>G)?

AlphaMissense predicts likely pathogenic (score 0.7386) — an in-silico prediction, not a clinical call.

TTI1 p.Thr22Arg

c.65C>G · VCV4855450

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7386 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with microcephaly and movement abnormalities

Computational evidence

Protein change
AlphaMissense	0.7386	likely pathogenic · top 10% in TTI1
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -12.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 30 kb · p 0.00063 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Thr22Arg
Coding: c.65C>G
MANE Select: NM_001303457
Type: single nucleotide variant
Location: chr20:38013752 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38 · 3 PDB

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.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.Trp279Gly Uncertain significance ★ ⚠ same condition
TTI1 c.2302+1G>T Pathogenic 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-thr22arg (accessed [today's date]).

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