TTI2 p.Asn46=

Q: Is TTI2 p.Asn46= (c.138T>C) pathogenic?

TTI2 p.Asn46= (c.138T>C) is classified Benign in TTI2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-09-10). Common (popmax 66.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome.

Q: What condition is associated with TTI2 p.Asn46= (c.138T>C)?

TTI2 p.Asn46= (c.138T>C) is associated with severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome (ClinVar).

Q: How common is TTI2 p.Asn46= (c.138T>C) in the general population?

TTI2 p.Asn46= (c.138T>C) is common (popmax 66.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.138T>C · rs3098657 · VCV1342858

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 66.8%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.87 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.4	GERP -4.2
Overall
CADD	1.794	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 66.8% African / African-American · 50,041/74,950 alleles

Filtering AF 66.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 66.1%

Overall 62.7% 1,011,956/1,613,874 alleles · common exomes 915,920/1,461,858 · genomes 96,036/152,016 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	66.8%	1
Amishnot grpmax-eligible	66.6%	2
Finnishnot grpmax-eligible	65%	2
European (non-Finnish)	64.4%	2
Remaining individualsnot grpmax-eligible	63.1%	2
Middle Eastern	61.1%	2
Ashkenazi Jewishnot grpmax-eligible	59.3%	2
East Asian	56.6%	2
South Asian	50.3%	2
Admixed American	47.1%	2

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.Asn46=
Coding: c.138T>C
MANE Select: NM_001102401
dbSNP: rs3098657
Type: single nucleotide variant
Location: chr8:33512476 (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

Disease context

severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TTI2 p.Asn46Ser Likely benign ★ same residue
TTI2 p.Arg334Gln Uncertain significance ★★ ⚠ same condition
TTI2 p.Arg355His Uncertain significance ★★ ⚠ same condition
TTI2 p.Thr232Ile Uncertain significance ★★ ⚠ same condition
TTI2 c.-99-31C>T Benign ★★ same condition
TTI2 p.Glu63Gly Benign ★★ same condition
TTI2 c.1115+1G>A Likely pathogenic ★ same condition
TTI2 c.1115+2T>C Likely 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/tti2-p-asn46 (accessed [today's date]).

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