Is TMPRSS2 p.Pro375Ser (c.1123C>T) pathogenic?

TMPRSS2 p.Pro375Ser (c.1123C>T) is classified Likely benign in TMPRSS2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-07-16). AlphaMissense: likely benign (0.1072); Rare (popmax 0.374%, afr); Associated with TMPRSS2-related disorder.

What condition is associated with TMPRSS2 p.Pro375Ser (c.1123C>T)?

TMPRSS2 p.Pro375Ser (c.1123C>T) is associated with TMPRSS2-related disorder (ClinVar).

How common is TMPRSS2 p.Pro375Ser (c.1123C>T) in the general population?

TMPRSS2 p.Pro375Ser (c.1123C>T) is rare (popmax 0.374%, afr) (gnomAD).

What do computational predictors say about TMPRSS2 p.Pro375Ser (c.1123C>T)?

AlphaMissense predicts likely benign (score 0.1072) — an in-silico prediction, not a clinical call.

TMPRSS2 p.Pro375Ser

c.1123C>T · rs61735795 · VCV3034163

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1072 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.374%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TMPRSS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1072	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -0.76, phastCons 0.99
Regional constraint	o/e 1.04	unconstrained · MANE · 32 kb · p 0.32 · regional, not allelic
Overall
CADD	9.616	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.374% African / African-American · 281/75,050 alleles

Filtering AF 0.338% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.324%

Overall 0.0195% 315/1,613,622 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.374%	267
Remaining individualsnot grpmax-eligible	0.0432%	2,315
Admixed American	0.01%	10,003
European (non-Finnish)	8.47e-05%	1,179,993

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: TMPRSS2
Protein: p.Pro375Ser
Coding: c.1123C>T
MANE Select: NM_005656
dbSNP: rs61735795
Type: single nucleotide variant
Location: chr21:41470696 (GRCh38)
Gene constraint: LOEUF 0.991 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 34 PDB
Residue 375: the peptidase s1 domain; the 'hku1-cov s protein-binding' region

Full TMPRSS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TMPRSS2-related disorder

Similar variants

TMPRSS2 p.Gly181Arg Likely benign ⚠ same condition
TMPRSS2 p.Gly325Arg Likely benign same condition
TMPRSS2 p.Ala216= Benign ★★ same type
TMPRSS2 p.Tyr180= Benign ★★ same type
TMPRSS2 p.Val160Met Benign ★★ same type
TMPRSS2 p.Ala490Gly Uncertain significance ★ ⚠ same type
TMPRSS2 p.Arg470Gly Uncertain significance ★ ⚠ same type
TMPRSS2 p.Asn249Asp Uncertain significance ★ ⚠ 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/tmprss2-p-pro375ser (accessed [today's date]).

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