Is TPP2 p.Val910Phe (c.2728G>T) pathogenic?

TPP2 p.Val910Phe (c.2728G>T) is classified Uncertain significance in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-28). AlphaMissense: likely pathogenic (0.6196); Very rare (popmax 0.000509%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TPP2 p.Val910Phe (c.2728G>T)?

TPP2 p.Val910Phe (c.2728G>T) is associated with Inborn genetic diseases (ClinVar).

How common is TPP2 p.Val910Phe (c.2728G>T) in the general population?

TPP2 p.Val910Phe (c.2728G>T) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about TPP2 p.Val910Phe (c.2728G>T)?

AlphaMissense predicts likely pathogenic (score 0.6196) — an in-silico prediction, not a clinical call.

TPP2 p.Val910Phe

c.2728G>T · rs2504039419 · VCV2314184

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6196 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6196	likely pathogenic
REVEL	0.142	moderately benign-leaning
SaProt	LLR -8.47	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 18 kb · p 7.8e-09 · regional, not allelic
Overall
CADD	25.1	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) · 6/1,179,884 alleles

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

Overall 0.000372% 6/1,613,780 alleles · very rare exomes 6/1,461,542 · genomes 0/152,238 · joint denominator

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.Val910Phe
Coding: c.2728G>T
MANE Select: NM_001330588
dbSNP: rs2504039419
Type: single nucleotide variant
Location: chr13:102649006 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 910: a UniProt-annotated variant site (in imd78; loss of expression)

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-val910phe (accessed [today's date]).

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