Is TPST2 p.Arg63His (c.188G>A) pathogenic?

TPST2 p.Arg63His (c.188G>A) is classified Uncertain significance in TPST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely benign (0.0799); Very rare (popmax 0.00516%, amr).

How common is TPST2 p.Arg63His (c.188G>A) in the general population?

TPST2 p.Arg63His (c.188G>A) is very rare (popmax 0.00516%, amr) (gnomAD).

What do computational predictors say about TPST2 p.Arg63His (c.188G>A)?

AlphaMissense predicts likely benign (score 0.0799) — an in-silico prediction, not a clinical call.

TPST2 p.Arg63His

c.188G>A · VCV3328363

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0799 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00516%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0799	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -9.09	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 4.8	GERP 0.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 13 kb · p 0.00068 · regional, not allelic
Overall
CADD	20.7	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 0.00516% Admixed American · 3/58,170 alleles

Filtering AF 0.00137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000679%

Overall 0.000749% 12/1,601,166 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00516%	19,390
African / African-American	0.00402%	24,884
East Asian	0.00223%	44,744
Remaining individualsnot grpmax-eligible	0.00162%	61,834
South Asian	0.00112%	88,990
European (non-Finnish)	0.000256%	391,308

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: TPST2
Protein: p.Arg63His
Coding: c.188G>A
MANE Select: NM_003595
Type: single nucleotide variant
Location: chr22:26541443 (GRCh38)
Gene constraint: LOEUF 0.957 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.18 · 5 PDB
Residue 63: a β-strand

Full TPST2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TPST2 p.Arg63Cys Uncertain significance ★ ⚠ same residue
TPST2 p.Ala126Val Uncertain significance ★ ⚠ same type
TPST2 p.Ala12Val Uncertain significance ★ ⚠ same type
TPST2 p.Ala152Ser Uncertain significance ★ ⚠ same type
TPST2 p.Ala263Ser Uncertain significance ★ ⚠ same type
TPST2 p.Ala297Val Uncertain significance ★ ⚠ same type
TPST2 p.Ala357Asp Uncertain significance ★ ⚠ same type
TPST2 p.Ala36Val Uncertain significance ★ ⚠ same type

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/tpst2-p-arg63his (accessed [today's date]).

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