Is TMPRSS3 p.Arg16Ter (c.46C>T) pathogenic?

TMPRSS3 p.Arg16Ter (c.46C>T) is classified Pathogenic/Likely pathogenic in TMPRSS3 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-01). Very rare (popmax 0.00445%, eas); Associated with autosomal recessive nonsyndromic hearing loss 8.

What condition is associated with TMPRSS3 p.Arg16Ter (c.46C>T)?

TMPRSS3 p.Arg16Ter (c.46C>T) is associated with autosomal recessive nonsyndromic hearing loss 8 (ClinVar).

How common is TMPRSS3 p.Arg16Ter (c.46C>T) in the general population?

TMPRSS3 p.Arg16Ter (c.46C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

TMPRSS3 p.Arg16Ter

c.46C>T · rs976363536 · VCV1210028

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Conditions

autosomal recessive nonsyndromic hearing loss 8

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 2 of 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -2.7, phastCons 1
Overall
CADD	37.0	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 0.00445% East Asian · 2/44,896 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.0013% 21/1,614,054 alleles · very rare exomes 20/1,461,866 · genomes 1/152,188 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,448
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.00144%	69,414
African / African-American	0.00133%	74,922

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.Arg16Ter
Coding: c.46C>T
MANE Select: NM_001256317
dbSNP: rs976363536
Type: single nucleotide variant
Location: chr21:42395372 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09

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

Disease context

autosomal recessive nonsyndromic hearing loss 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMPRSS3 p.Arg16Gln Uncertain significance ★★ ⚠ same residue
TMPRSS3 p.Arg16Leu Uncertain significance ★ ⚠ same residue
TMPRSS3 p.Arg16= Likely benign ★ same residue
TMPRSS3 c.1049-4G>A Likely pathogenic ★★ same condition
TMPRSS3 c.206-2A>G Likely pathogenic ★★ same condition
TMPRSS3 c.323-6G>A Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 c.446+1G>T Likely pathogenic ★★ same condition
TMPRSS3 c.573-1G>A 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-arg16ter (accessed [today's date]).

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