Is TPP2 p.Asn925Ser (c.2774A>G) pathogenic?

TPP2 p.Asn925Ser (c.2774A>G) is classified Uncertain significance in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-06). AlphaMissense: likely benign (0.0827); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TPP2 p.Asn925Ser (c.2774A>G)?

TPP2 p.Asn925Ser (c.2774A>G) is associated with Inborn genetic diseases (ClinVar).

How common is TPP2 p.Asn925Ser (c.2774A>G) in the general population?

TPP2 p.Asn925Ser (c.2774A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TPP2 p.Asn925Ser (c.2774A>G)?

AlphaMissense predicts likely benign (score 0.0827) — an in-silico prediction, not a clinical call.

TPP2 p.Asn925Ser

c.2774A>G · VCV4633470

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0827 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0827	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -4.50	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 6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 18 kb · p 7.8e-09 · regional, not allelic
Overall
CADD	14.52	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TPP2
Protein: p.Asn925Ser
Coding: c.2774A>G
MANE Select: NM_001330588
Type: single nucleotide variant
Location: chr13:102649052 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 925: 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-asn925ser (accessed [today's date]).

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