Is TMPRSS9 p.Arg1007Pro (c.3020G>C) pathogenic?

TMPRSS9 p.Arg1007Pro (c.3020G>C) is classified Uncertain significance in TMPRSS9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely benign (0.2445); Very rare (popmax 8.62e-05%, nfe).

How common is TMPRSS9 p.Arg1007Pro (c.3020G>C) in the general population?

TMPRSS9 p.Arg1007Pro (c.3020G>C) is very rare (popmax 8.62e-05%, nfe) (gnomAD).

What do computational predictors say about TMPRSS9 p.Arg1007Pro (c.3020G>C)?

AlphaMissense predicts likely benign (score 0.2445) — an in-silico prediction, not a clinical call.

TMPRSS9 p.Arg1007Pro

c.3020G>C · VCV4187596

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2445 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.62e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2445	likely benign
REVEL	0.545	indeterminate
SaProt	LLR -8.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -2.2, phastCons 1
Overall
CADD	24.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R973P vs ClinVar R1007P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.62e-05% European (non-Finnish) · 1/1,160,494 alleles

Overall 6.42e-05% 1/1,557,182 alleles · very rare exomes 1/1,405,058 · genomes 0/152,124 · joint denominator

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: TMPRSS9
Protein: p.Arg1007Pro
Coding: c.3020G>C
MANE Select: NM_001395513
Type: single nucleotide variant
Location: chr19:2425393 (GRCh38)
Gene constraint: LOEUF 1.326 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.96
Residue 973 UniProt numbering: the peptidase s1 3 domain

Full TMPRSS9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TMPRSS9 p.Arg1007Cys Uncertain significance ★ ⚠ same residue
TMPRSS9 p.Arg433Trp Uncertain significance ★★ ⚠ same type
TMPRSS9 p.Asp324Asn Uncertain significance ★★ ⚠ same type
TMPRSS9 p.Pro752Leu Uncertain significance ★★ ⚠ same type
TMPRSS9 p.Ser780Leu Uncertain significance ★★ ⚠ same type
TMPRSS9 p.Ala449Thr Benign ★★ same type
TMPRSS9 p.Ala682= Benign ★★ same type
TMPRSS9 p.Gly832Arg Benign/Likely 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/tmprss9-p-arg1007pro (accessed [today's date]).

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