Is TPST2 p.Arg85His (c.254G>A) pathogenic?

TPST2 p.Arg85His (c.254G>A) is classified Uncertain significance in TPST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). AlphaMissense: likely pathogenic (0.9925); Very rare (popmax 0.00295%, nfe).

How common is TPST2 p.Arg85His (c.254G>A) in the general population?

TPST2 p.Arg85His (c.254G>A) is very rare (popmax 0.00295%, nfe) (gnomAD).

What do computational predictors say about TPST2 p.Arg85His (c.254G>A)?

AlphaMissense predicts likely pathogenic (score 0.9925) — an in-silico prediction, not a clinical call.

TPST2 p.Arg85His

c.254G>A · VCV3972747

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00295%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9925	likely pathogenic
REVEL	0.564	indeterminate
SaProt	LLR -14.45	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 13 kb · p 0.00068 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00295% European (non-Finnish) · 34/1,151,030 alleles

Filtering AF 0.00213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00188%

Overall 0.00225% 35/1,557,566 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00295%	33,854
Remaining individualsnot grpmax-eligible	0.00167%	59,924

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.Arg85His
Coding: c.254G>A
MANE Select: NM_003595
Type: single nucleotide variant
Location: chr22:26541377 (GRCh38)
Gene constraint: LOEUF 0.957 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.18 · 5 PDB
Residue 85: an α-helix

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

Similar variants

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
TPST2 p.Ala44Thr 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-arg85his (accessed [today's date]).

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