Is TPP2 p.Val317Ile (c.949G>A) pathogenic?

TPP2 p.Val317Ile (c.949G>A) is classified Uncertain significance in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.1877); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TPP2 p.Val317Ile (c.949G>A)?

TPP2 p.Val317Ile (c.949G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TPP2 p.Val317Ile (c.949G>A) in the general population?

TPP2 p.Val317Ile (c.949G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TPP2 p.Val317Ile (c.949G>A)?

AlphaMissense predicts likely benign (score 0.1877) — an in-silico prediction, not a clinical call.

TPP2 p.Val317Ile

c.949G>A · VCV4633473

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1877 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1877	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -8.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.47	acceptor loss, 9 bp away · masked 0 · deltas
Pangolin	Δ0.39	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 31 kb · p 8.5e-07 · regional, not allelic
Overall
CADD	21.4	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,310 alleles

Overall 6.85e-05% 1/1,460,502 alleles · very rare

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.Val317Ile
Coding: c.949G>A
MANE Select: NM_001330588
Type: single nucleotide variant
Location: chr13:102627857 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 317: the peptidase s8 domain

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.Val317Phe Uncertain significance ★ ⚠ same residue
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

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-val317ile (accessed [today's date]).

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