Is TPP2 p.Val317Phe (c.949G>T) pathogenic?

TPP2 p.Val317Phe (c.949G>T) is classified Uncertain significance in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-28). AlphaMissense: likely pathogenic (0.9033); Very rare (popmax 0.000509%, nfe); Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

How common is TPP2 p.Val317Phe (c.949G>T) in the general population?

TPP2 p.Val317Phe (c.949G>T) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about TPP2 p.Val317Phe (c.949G>T)?

AlphaMissense predicts likely pathogenic (score 0.9033) — an in-silico prediction, not a clinical call.

TPP2 p.Val317Phe

Q: What condition is associated with TPP2 p.Val317Phe (c.949G>T)?

TPP2 p.Val317Phe (c.949G>T) is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (ClinVar).

c.949G>T · rs1566337078 · VCV1938418

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9033 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency

Computational evidence

Protein change
AlphaMissense	0.9033	likely pathogenic
REVEL	0.209	benign-leaning
SaProt	LLR -13.78	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.55	acceptor loss, 9 bp away · masked 0 · deltas
Pangolin	Δ0.46	loss · gain 0.01 · 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	23.8	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 0.000509% European (non-Finnish) · 6/1,179,310 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000411% 6/1,460,502 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.Val317Phe
Coding: c.949G>T
MANE Select: NM_001330588
dbSNP: rs1566337078
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

Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TPP2 p.Val317Ile Uncertain significance ★ ⚠ same residue
TPP2 p.Ala619Thr Uncertain significance ★★ ⚠ same condition
TPP2 p.Ala648Asp Uncertain significance ★★ ⚠ same condition
TPP2 p.Arg1072Gln Uncertain significance ★★ ⚠ same condition
TPP2 p.Arg893Cys Uncertain significance ★★ ⚠ same condition
TPP2 p.Asn1192Ser Uncertain significance ★★ ⚠ same condition
TPP2 p.Asn1227Ser Uncertain significance ★★ ⚠ same condition
TPP2 p.Asp86His 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-val317phe (accessed [today's date]).

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