Is TTI2 p.Glu63Gly (c.188A>G) pathogenic?

TTI2 p.Glu63Gly (c.188A>G) is classified Benign in TTI2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-09-10). AlphaMissense: likely benign (0.0808); Common (popmax 61.7%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome.

What do computational predictors say about TTI2 p.Glu63Gly (c.188A>G)?

AlphaMissense predicts likely benign (score 0.0808) — an in-silico prediction, not a clinical call.

TTI2 p.Glu63Gly

Q: What condition is associated with TTI2 p.Glu63Gly (c.188A>G)?

TTI2 p.Glu63Gly (c.188A>G) is associated with severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome (ClinVar).

Q: How common is TTI2 p.Glu63Gly (c.188A>G) in the general population?

TTI2 p.Glu63Gly (c.188A>G) is common (popmax 61.7%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.188A>G · rs2304748 · VCV1342857

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0808 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 61.7%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0808	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -6.86	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 0.59	GERP -1.4, phastCons 0.32
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	15.11	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 61.7% European (non-Finnish) · 727,759/1,179,968 alleles

Filtering AF 61.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 61.5%

Overall 59.2% 955,835/1,613,788 alleles · common exomes 871,830/1,461,854 · genomes 84,005/151,934 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	66%	2
Finnishnot grpmax-eligible	63.2%	2
European (non-Finnish)grpmax	61.7%	2
Remaining individualsnot grpmax-eligible	59.4%	2
Middle Eastern	57.7%	2
Ashkenazi Jewishnot grpmax-eligible	57.3%	2
East Asian	56.5%	2
South Asian	48.2%	2
African / African-American	45.3%	2
Admixed American	43.9%	2

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu63Gly
Coding: c.188A>G
MANE Select: NM_001102401
dbSNP: rs2304748
Type: single nucleotide variant
Location: chr8:33512426 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.85 · 2 PDB
Residue 63: a UniProt-annotated variant site (in)

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.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.Asn46= Benign ★★ same condition
TTI2 c.1115+1G>A Likely pathogenic ★ same condition
TTI2 c.1115+2T>C Likely pathogenic ★ same condition
TTI2 p.Asp317Val 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-glu63gly (accessed [today's date]).

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