Is TMPRSS3 p.Met447fs (c.1335_1339dup) pathogenic?

TMPRSS3 p.Met447fs (c.13351339dup) is classified Pathogenic in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-18). Very rare (popmax 0.000678%, nfe).

How common is TMPRSS3 p.Met447fs (c.1335_1339dup) in the general population?

TMPRSS3 p.Met447fs (c.1335_1339dup) is very rare (popmax 0.000678%, nfe) (gnomAD).

TMPRSS3 p.Met447fs

c.1335_1339dup · rs1351236437 · VCV1909242

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (12 of 13, 4 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,180,006 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,552 alleles · very rare exomes 7/1,461,502 · genomes 1/152,050 · 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: TMPRSS3
Protein: p.Met447fs
Coding: c.1335_1339dup
MANE Select: NM_001256317
dbSNP: rs1351236437
Type: Duplication
Location: chr21:42375720 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 447: the peptidase s1 domain

Full TMPRSS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TMPRSS3 p.Met447Thr Pathogenic/Likely pathogenic ★★ same residue
TMPRSS3 p.Cys194fs Pathogenic/Likely pathogenic ★★ same type
TMPRSS3 c.617-3_617-2dup Benign ★★ same type
TMPRSS3 p.Pro403fs Likely pathogenic ★ same type
TMPRSS3 p.Pro50fs Pathogenic ★ same type
TMPRSS3 p.Ser14fs Pathogenic ★ same type
TMPRSS3 c.573-157_573-156dup Benign ★ same type
TMPRSS3 c.573-157dup 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/tmprss3-p-met447fs (accessed [today's date]).

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