Is TPSAB1 p.Ala196Pro (c.586G>C) pathogenic?

TPSAB1 p.Ala196Pro (c.586G>C) is classified Uncertain significance in TPSAB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). AlphaMissense: likely benign (0.2047); Ultra-rare (popmax 0.0227%, amr).

How common is TPSAB1 p.Ala196Pro (c.586G>C) in the general population?

TPSAB1 p.Ala196Pro (c.586G>C) is ultra-rare (popmax 0.0227%, amr) (gnomAD).

What do computational predictors say about TPSAB1 p.Ala196Pro (c.586G>C)?

AlphaMissense predicts likely benign (score 0.2047) — an in-silico prediction, not a clinical call.

TPSAB1 p.Ala196Pro

c.586G>C · VCV3809875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2047 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, amr)

Computational evidence

Protein change
AlphaMissense	0.2047	likely benign
REVEL	0.439	indeterminate
SaProt	—	withheld · numbering disagrees past residue 51 · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -2.6
Regional constraint	o/e 0.81	unconstrained · MANE · 543 bp · p 0.059 · regional, not allelic
Overall
CADD	0.726	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% Admixed American · 5/22,030 alleles

Filtering AF 0.00891% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00317% 17/536,132 alleles · ultra-rare exomes 17/499,758 · genomes 0/36,374 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0227%	4,406
Remaining individualsnot grpmax-eligible	0.00711%	14,067
European (non-Finnish)	0.00299%	33,497

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: TPSAB1
Protein: p.Ala196Pro
Coding: c.586G>C
MANE Select: NM_003294
Type: single nucleotide variant
Location: chr16:1241913 (GRCh38)
Gene constraint: LOEUF 1.9 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.80 · 22 PDB
Residue 196: the peptidase s1 domain; a β-strand

Full TPSAB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TPSAB1 p.Ala196Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
TPSAB1 p.Val76Met Uncertain significance ★★ same type
TPSAB1 c.1-105C>A Benign ★★ same type
TPSAB1 c.233+12G>A Benign ★★ same type
TPSAB1 c.233+30G>C Benign ★★ same type
TPSAB1 c.61+75T>C Benign ★★ same type
TPSAB1 c.62-27C>T Benign ★★ same type
TPSAB1 c.62-40C>G Benign ★★ 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/tpsab1-p-ala196pro (accessed [today's date]).

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