Is TPSAB1 p.Pro103Arg (c.308C>G) pathogenic?

TPSAB1 p.Pro103Arg (c.308C>G) is classified Uncertain significance in TPSAB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). AlphaMissense: likely benign (0.139); Very rare (popmax 0.00243%, sas).

How common is TPSAB1 p.Pro103Arg (c.308C>G) in the general population?

TPSAB1 p.Pro103Arg (c.308C>G) is very rare (popmax 0.00243%, sas) (gnomAD).

What do computational predictors say about TPSAB1 p.Pro103Arg (c.308C>G)?

AlphaMissense predicts likely benign (score 0.139) — an in-silico prediction, not a clinical call.

TPSAB1 p.Pro103Arg

c.308C>G · VCV3460587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.139 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00243%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.139	likely benign
REVEL	0.438	indeterminate
SaProt	LLR -5.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP -20	GERP -3.4
Regional constraint	o/e 0.10	constrained · MANE · 374 bp · p 2.3e-20 · regional, not allelic
Overall
CADD	4.245	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 0.00243% South Asian · 2/82,142 alleles

Filtering AF 0.000404% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000151%

Overall 0.000218% 3/1,375,920 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00243%	41,071
European (non-Finnish)	8.88e-05%	1,126,012

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.Pro103Arg
Coding: c.308C>G
MANE Select: NM_003294
Type: single nucleotide variant
Location: chr16:1241508 (GRCh38)
Gene constraint: LOEUF 1.9 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.80 · 22 PDB
Residue 103: the peptidase s1 domain

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

Similar variants

TPSAB1 p.Pro103Leu Uncertain significance ★ ⚠ same residue
TPSAB1 p.Pro103= Likely benign ★ 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

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-pro103arg (accessed [today's date]).

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