Is TTI2 p.Thr417Ser (c.1250C>G) pathogenic?

TTI2 p.Thr417Ser (c.1250C>G) is classified Likely benign in TTI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-06). AlphaMissense: likely benign (0.1345); Rare (popmax 0.753%, sas).

How common is TTI2 p.Thr417Ser (c.1250C>G) in the general population?

TTI2 p.Thr417Ser (c.1250C>G) is rare (popmax 0.753%, sas) (gnomAD).

What do computational predictors say about TTI2 p.Thr417Ser (c.1250C>G)?

AlphaMissense predicts likely benign (score 0.1345) — an in-silico prediction, not a clinical call.

TTI2 p.Thr417Ser

c.1250C>G · rs199664580 · VCV1336577

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1345 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.753%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1345	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -2.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.9, phastCons 0.83
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	19.7	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 0.753% South Asian · 686/91,086 alleles

Filtering AF 0.706% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.688%

Overall 0.0446% 720/1,614,164 alleles · rare exomes 686/1,461,882 · genomes 34/152,282 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.753%	133
Remaining individualsnot grpmax-eligible	0.04%	2,500
Admixed American	0.00167%	60,010
African / African-American	0.00133%	75,040
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: TTI2
Protein: p.Thr417Ser
Coding: c.1250C>G
MANE Select: NM_001102401
dbSNP: rs199664580
Type: single nucleotide variant
Location: chr8:33503438 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.85 · 2 PDB

Full TTI2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TTI2 p.Arg334Gln Uncertain significance ★★ ⚠ same type
TTI2 p.Arg355His Uncertain significance ★★ ⚠ same type
TTI2 p.Arg379Trp Uncertain significance ★★ ⚠ same type
TTI2 p.Gly190Val Uncertain significance ★★ ⚠ same type
TTI2 p.Pro149Leu Uncertain significance ★★ ⚠ same type
TTI2 p.Thr232Ile Uncertain significance ★★ ⚠ same type
TTI2 p.Thr237Ala Uncertain significance ★★ ⚠ same type
TTI2 c.-99-31C>T Benign ★★ 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/tti2-p-thr417ser (accessed [today's date]).

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