Is TMPRSS3 p.Ser153Ter (c.458C>G) pathogenic?

TMPRSS3 p.Ser153Ter (c.458C>G) is classified Pathogenic/Likely pathogenic in TMPRSS3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-15). Very rare (popmax 0.00167%, amr); Associated with TMPRSS3-related disorder.

What condition is associated with TMPRSS3 p.Ser153Ter (c.458C>G)?

TMPRSS3 p.Ser153Ter (c.458C>G) is associated with TMPRSS3-related disorder (ClinVar).

How common is TMPRSS3 p.Ser153Ter (c.458C>G) in the general population?

TMPRSS3 p.Ser153Ter (c.458C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

TMPRSS3 p.Ser153Ter

c.458C>G · rs909821850 · VCV2882012

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

TMPRSS3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 13
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.31	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 9.6	GERP 1.7, phastCons 1
Overall
CADD	38.0	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 0.00167% Admixed American · 1/60,008 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,614,012 alleles · very rare exomes 5/1,461,832 · genomes 1/152,180 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,008
European (non-Finnish)	0.000424%	236,002

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.Ser153Ter
Coding: c.458C>G
MANE Select: NM_001256317
dbSNP: rs909821850
Type: single nucleotide variant
Location: chr21:42385523 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 153: the srcr domain

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

Disease context

TMPRSS3-related disorder

Similar variants

TMPRSS3 c.323-6G>A Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Ala138Glu Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Ala306Thr Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Ala425Thr Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Arg109Trp Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Arg91Ter Pathogenic ★★ same condition
TMPRSS3 p.Val116Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
TMPRSS3 c.616+2T>C Likely pathogenic ★ same condition

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-ser153ter (accessed [today's date]).

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