Is TMPRSS3 p.Ter454Arg (c.1360T>C) pathogenic?

TMPRSS3 p.Ter454Arg (c.1360T>C) is classified Conflicting classifications of pathogenicity in TMPRSS3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-09-09). Rare (popmax 0.323%, afr); Associated with autosomal recessive nonsyndromic hearing loss 8.

What condition is associated with TMPRSS3 p.Ter454Arg (c.1360T>C)?

TMPRSS3 p.Ter454Arg (c.1360T>C) is associated with autosomal recessive nonsyndromic hearing loss 8 (ClinVar).

How common is TMPRSS3 p.Ter454Arg (c.1360T>C) in the general population?

TMPRSS3 p.Ter454Arg (c.1360T>C) is rare (popmax 0.323%, afr) (gnomAD).

TMPRSS3 p.Ter454Arg

c.1360T>C · rs149919890 · VCV1032152

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

stop-loss

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.323%, afr)

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	stop-loss	predicted loss-of-function
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1, phastCons 1
Overall
CADD	10.3	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 0.323% African / African-American · 242/74,962 alleles

Filtering AF 0.289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.276%

Overall 0.0168% 271/1,613,924 alleles · rare exomes 131/1,461,840 · genomes 140/152,084 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.323%	310
Admixed American	0.0233%	4,286
Remaining individualsnot grpmax-eligible	0.0176%	5,682
South Asian	0.0022%	45,534
European (non-Finnish)	0.000169%	589,974

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.Ter454Arg
Coding: c.1360T>C
MANE Select: NM_001256317
dbSNP: rs149919890
Type: single nucleotide variant
Location: chr21:42372764 (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 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
TMPRSS3 p.Ala138Glu Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Ala306Thr Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Ala306Val 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-ter454arg (accessed [today's date]).

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