Is TTI2 p.Leu425Arg (c.1274T>G) pathogenic?

TTI2 p.Leu425Arg (c.1274T>G) is classified Conflicting classifications of pathogenicity in TTI2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.1045); Low-frequency (popmax 1.07%, eas).

How common is TTI2 p.Leu425Arg (c.1274T>G) in the general population?

TTI2 p.Leu425Arg (c.1274T>G) is low-frequency (popmax 1.07%, eas) (gnomAD).

What do computational predictors say about TTI2 p.Leu425Arg (c.1274T>G)?

AlphaMissense predicts likely benign (score 0.1045) — an in-silico prediction, not a clinical call.

TTI2 p.Leu425Arg

c.1274T>G · rs3736497 · VCV437080

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1045 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.07%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1045	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -8.01	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 5.3	GERP 0.29, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	22.5	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 1.07% East Asian · 481/44,888 alleles

Filtering AF 0.992% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.961%

Overall 0.0337% 544/1,614,162 alleles · low-frequency exomes 491/1,461,830 · genomes 53/152,332 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.07%	93
Remaining individualsnot grpmax-eligible	0.0576%	1,736
Admixed American	0.01%	10,003
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
South Asian	0.00549%	18,217
European (non-Finnish)	0.00119%	84,287

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.Leu425Arg
Coding: c.1274T>G
MANE Select: NM_001102401
dbSNP: rs3736497
Type: single nucleotide variant
Location: chr8:33500476 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.85 · 2 PDB
Residue 425: a UniProt-annotated variant site (in)

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

Similar variants

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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-leu425arg (accessed [today's date]).

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