Is TPST2 p.Arg42Trp (c.124C>T) pathogenic?

TPST2 p.Arg42Trp (c.124C>T) is classified Uncertain significance in TPST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely benign (0.117); Ultra-rare (popmax 0.0107%, afr).

How common is TPST2 p.Arg42Trp (c.124C>T) in the general population?

TPST2 p.Arg42Trp (c.124C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about TPST2 p.Arg42Trp (c.124C>T)?

AlphaMissense predicts likely benign (score 0.117) — an in-silico prediction, not a clinical call.

TPST2 p.Arg42Trp

c.124C>T · rs538180758 · VCV2531555

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.117 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.117	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -8.98	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 0.29	GERP -2.9
Regional constraint	o/e 0.85	unconstrained · MANE · 13 kb · p 0.00068 · regional, not allelic
Overall
CADD	16.85	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 0.0107% African / African-American · 8/74,990 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000621% 10/1,611,478 alleles · ultra-rare exomes 7/1,459,120 · genomes 3/152,358 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,374
Remaining individualsnot grpmax-eligible	0.0016%	62,382
European (non-Finnish)	8.48e-05%	1,178,907

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.Arg42Trp
Coding: c.124C>T
MANE Select: NM_003595
dbSNP: rs538180758
Type: single nucleotide variant
Location: chr22:26541507 (GRCh38)
Gene constraint: LOEUF 0.957 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.18 · 5 PDB

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

Similar variants

TPST2 p.Arg42Gln 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-arg42trp (accessed [today's date]).

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