Is TMPRSS3 p.Thr248= (c.744G>A) pathogenic?

TMPRSS3 p.Thr248= (c.744G>A) is classified Likely benign in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). Ultra-rare (popmax 0.0164%, mid).

How common is TMPRSS3 p.Thr248= (c.744G>A) in the general population?

TMPRSS3 p.Thr248= (c.744G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

TMPRSS3 p.Thr248=

c.744G>A · rs369903582 · VCV2899980

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

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 -2.8	GERP -5
Overall
CADD	2.68	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

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

Overall 0.00322% 52/1,614,034 alleles · ultra-rare exomes 46/1,461,804 · genomes 6/152,230 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0641%	1,560
Middle Easterngrpmax	0.0164%	6,084
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Admixed American	0.00167%	60,010
African / African-American	0.00133%	74,924
European (non-Finnish)	0.000424%	236,012

Finnish 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: TMPRSS3
Protein: p.Thr248=
Coding: c.744G>A
MANE Select: NM_001256317
dbSNP: rs369903582
Type: single nucleotide variant
Location: chr21:42383071 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 248: the peptidase s1 domain

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

Similar variants

TMPRSS3 p.Thr248Met Pathogenic/Likely pathogenic ★★ ⚠ same residue
TMPRSS3 c.1049-4G>A Likely pathogenic ★★ same type
TMPRSS3 c.206-2A>G Likely pathogenic ★★ same type
TMPRSS3 c.323-6G>A Pathogenic/Likely pathogenic ★★ same type
TMPRSS3 c.446+1G>T Likely pathogenic ★★ same type
TMPRSS3 c.573-1G>A Likely pathogenic ★★ same type
TMPRSS3 p.Ala138Glu Pathogenic/Likely pathogenic ★★ same type
TMPRSS3 p.Ala306Thr Pathogenic/Likely pathogenic ★★ 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-thr248 (accessed [today's date]).

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