Is TMPRSS9 p.Pro249= (c.747G>A) pathogenic?

TMPRSS9 p.Pro249= (c.747G>A) is classified Likely benign in TMPRSS9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-01). Ultra-rare (popmax 0.043%, nfe).

How common is TMPRSS9 p.Pro249= (c.747G>A) in the general population?

TMPRSS9 p.Pro249= (c.747G>A) is ultra-rare (popmax 0.043%, nfe) (gnomAD).

TMPRSS9 p.Pro249=

c.747G>A · rs149559028 · VCV2648972

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.043%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.1	GERP -3.9
Overall
CADD	0.408	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.043% European (non-Finnish) · 507/1,178,082 alleles

Filtering AF 0.0399% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0386%

Overall 0.0351% 565/1,607,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0441%	2,266
European (non-Finnish)grpmax	0.043%	2,324
Remaining individualsnot grpmax-eligible	0.0257%	3,886
Finnishnot grpmax-eligible	0.0219%	4,568
Admixed American	0.00683%	14,640
South Asian	0.00665%	15,037
African / African-American	0.00537%	18,627
East Asian	0.00228%	43,942

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro249=
Coding: c.747G>A
MANE Select: NM_001395513
dbSNP: rs149559028
Type: single nucleotide variant
Location: chr19:2405450 (GRCh38)
Gene constraint: LOEUF 1.326 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.96
Residue 249: the peptidase s1 1 domain

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

Similar variants

TMPRSS9 p.Pro249Leu 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-pro249 (accessed [today's date]).

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