Is TPP2 p.Val1261Ile (c.3781G>A) pathogenic?

TPP2 p.Val1261Ile (c.3781G>A) is classified Uncertain significance in TPP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-06). AlphaMissense: likely benign (0.064); Very rare (popmax 0.00668%, amr); Associated with Inborn genetic diseases.

What condition is associated with TPP2 p.Val1261Ile (c.3781G>A)?

TPP2 p.Val1261Ile (c.3781G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TPP2 p.Val1261Ile (c.3781G>A) in the general population?

TPP2 p.Val1261Ile (c.3781G>A) is very rare (popmax 0.00668%, amr) (gnomAD).

What do computational predictors say about TPP2 p.Val1261Ile (c.3781G>A)?

AlphaMissense predicts likely benign (score 0.064) — an in-silico prediction, not a clinical call.

TPP2 p.Val1261Ile

c.3781G>A · rs368359506 · VCV850271

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.064 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.064	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -5.49	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 9.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 2,009 bp · p 2.5e-05 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V1248I vs ClinVar V1261I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% Admixed American · 4/59,906 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00273% 44/1,612,918 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00668%	14,976
South Asian	0.0055%	18,179
Remaining individualsnot grpmax-eligible	0.00481%	20,807
East Asian	0.00446%	22,432
European (non-Finnish)	0.00254%	39,317

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: TPP2
Protein: p.Val1261Ile
Coding: c.3781G>A
MANE Select: NM_001330588
dbSNP: rs368359506
Type: single nucleotide variant
Location: chr13:102678308 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98

Full TPP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TPP2 p.Ala1143Ser Uncertain significance ★★ ⚠ same condition
TPP2 p.Ala460Thr Uncertain significance ★★ ⚠ same condition
TPP2 p.Arg598His Uncertain significance ★★ ⚠ same condition
TPP2 p.Arg902His Uncertain significance ★★ ⚠ same condition
TPP2 p.Asn771Ser Uncertain significance ★★ ⚠ same condition
TPP2 p.Cys710Tyr Uncertain significance ★★ ⚠ same condition
TPP2 p.Gln290Arg Uncertain significance ★★ ⚠ same condition
TPP2 p.Glu132Lys Uncertain significance ★★ ⚠ 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/tpp2-p-val1261ile (accessed [today's date]).

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