Is TPRKB p.Ser99Ala (c.295T>G) pathogenic?

TPRKB p.Ser99Ala (c.295T>G) is classified Uncertain significance in TPRKB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-01). AlphaMissense: likely benign (0.0777); Very rare (popmax 0.00257%, sas); Associated with Galloway-Mowat syndrome 5.

What condition is associated with TPRKB p.Ser99Ala (c.295T>G)?

TPRKB p.Ser99Ala (c.295T>G) is associated with Galloway-Mowat syndrome 5 (ClinVar).

How common is TPRKB p.Ser99Ala (c.295T>G) in the general population?

TPRKB p.Ser99Ala (c.295T>G) is very rare (popmax 0.00257%, sas) (gnomAD).

What do computational predictors say about TPRKB p.Ser99Ala (c.295T>G)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

TPRKB p.Ser99Ala

c.295T>G · VCV3897979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00257%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Galloway-Mowat syndrome 5

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -7.30	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 7.2	GERP 1.9, phastCons 1
Overall
CADD	18.54	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 0.00257% South Asian · 2/77,950 alleles

Filtering AF 0.000426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000131% 2/1,529,170 alleles · very rare exomes 2/1,377,186 · genomes 0/151,984 · 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: TPRKB
Protein: p.Ser99Ala
Coding: c.295T>G
MANE Select: NM_016058
Type: single nucleotide variant
Location: chr2:73730706 (GRCh38)
Structure: AlphaFold pLDDT 91.58 · 6 PDB
Residue 99: the protein kinase domain

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

Disease context

Galloway-Mowat syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TP53RK p.Pro99= Likely benign ★ same residue
TPRKB p.Tyr149His Uncertain significance ★★ same condition
TPRKB p.Gln130= Benign/Likely benign ★★ same condition
TPRKB p.Ile158= Benign ★★ same condition
TPRKB p.Tyr149Asn Likely pathogenic ★ same condition
TPRKB p.Tyr149Cys Pathogenic ⚠ same condition
TPRKB p.Leu136Pro Conflicting classifications of pathogenicity ⚠ same condition
TPRKB p.Arg31del 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/tprkb-p-ser99ala (accessed [today's date]).

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