Is TMPRSS9 p.Ser596Phe (c.1787C>T) pathogenic?

TMPRSS9 p.Ser596Phe (c.1787C>T) is classified Uncertain significance in TMPRSS9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-28). AlphaMissense: likely benign (0.2311); Absent from gnomAD v4.1.

How common is TMPRSS9 p.Ser596Phe (c.1787C>T) in the general population?

TMPRSS9 p.Ser596Phe (c.1787C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMPRSS9 p.Ser596Phe (c.1787C>T)?

AlphaMissense predicts likely benign (score 0.2311) — an in-silico prediction, not a clinical call.

TMPRSS9 p.Ser596Phe

c.1787C>T · rs2512192920 · VCV3179969

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2311 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2311	likely benign
REVEL	0.272	benign-leaning
SaProt	LLR -8.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.8	GERP 1.6, phastCons 1
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S562F vs ClinVar S596F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMPRSS9
Protein: p.Ser596Phe
Coding: c.1787C>T
MANE Select: NM_001395513
dbSNP: rs2512192920
Type: single nucleotide variant
Location: chr19:2416579 (GRCh38)
Gene constraint: LOEUF 1.326 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.96
Residue 562 UniProt numbering: the peptidase s1 2 domain

Full TMPRSS9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TMPRSS9 p.Arg433Trp Uncertain significance ★★ ⚠ same type
TMPRSS9 p.Asp324Asn Uncertain significance ★★ ⚠ same type
TMPRSS9 p.Pro752Leu Uncertain significance ★★ ⚠ same type
TMPRSS9 p.Ser780Leu Uncertain significance ★★ ⚠ same type
TMPRSS9 p.Ala449Thr Benign ★★ same type
TMPRSS9 p.Ala682= Benign ★★ same type
TMPRSS9 p.Gly832Arg Benign/Likely benign ★★ same type
TMPRSS9 p.Ile968Val Benign ★★ 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/tmprss9-p-ser596phe (accessed [today's date]).

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