Is TTI2 p.Pro40Ser (c.118C>T) pathogenic?

TTI2 p.Pro40Ser (c.118C>T) is classified Benign/Likely benign in TTI2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.0915); Rare (popmax 0.869%, nfe).

How common is TTI2 p.Pro40Ser (c.118C>T) in the general population?

TTI2 p.Pro40Ser (c.118C>T) is rare (popmax 0.869%, nfe) (gnomAD).

What do computational predictors say about TTI2 p.Pro40Ser (c.118C>T)?

AlphaMissense predicts likely benign (score 0.0915) — an in-silico prediction, not a clinical call.

TTI2 p.Pro40Ser

c.118C>T · rs78781527 · VCV437085

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0915 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.869%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0915	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.97	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 7.1	GERP 0.13, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	11.19	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 0.869% European (non-Finnish) · 10,257/1,180,038 alleles

Filtering AF 0.855% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.849%

Overall 0.708% 11,427/1,614,082 alleles · rare exomes 10,668/1,461,882 · genomes 759/152,200 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.869%	115
Remaining individualsnot grpmax-eligible	0.624%	160
Ashkenazi Jewishnot grpmax-eligible	0.564%	177
Admixed American	0.36%	278
Finnishnot grpmax-eligible	0.244%	410
African / African-American	0.156%	641
South Asian	0.127%	785
Middle Eastern	0.115%	866
Amishnot grpmax-eligible	0.11%	912

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.Pro40Ser
Coding: c.118C>T
MANE Select: NM_001102401
dbSNP: rs78781527
Type: single nucleotide variant
Location: chr8:33512496 (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.Pro40Leu Uncertain significance ★ ⚠ same residue
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

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-pro40ser (accessed [today's date]).

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