Is TMPRSS15 p.Ser46Phe (c.137C>T) pathogenic?

TMPRSS15 p.Ser46Phe (c.137C>T) is classified Uncertain significance in TMPRSS15 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-07). AlphaMissense: likely benign (0.1273); Absent from gnomAD v4.1.

How common is TMPRSS15 p.Ser46Phe (c.137C>T) in the general population?

TMPRSS15 p.Ser46Phe (c.137C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMPRSS15 p.Ser46Phe (c.137C>T)?

AlphaMissense predicts likely benign (score 0.1273) — an in-silico prediction, not a clinical call.

TMPRSS15 p.Ser46Phe

c.137C>T · rs2076115776 · VCV1974248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1273 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1273	likely benign
REVEL	0.396	indeterminate
SaProt	LLR -6.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.94, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 134 kb · p 0.043 · regional, not allelic
Overall
CADD	18.31	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.

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: TMPRSS15
Protein: p.Ser46Phe
Coding: c.137C>T
MANE Select: NM_002772
dbSNP: rs2076115776
Type: single nucleotide variant
Location: chr21:18403486 (GRCh38)
Gene constraint: LOEUF 1.12 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.03 · 14 PDB

Full TMPRSS15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TMPRSS15 c.1922-1G>A Likely pathogenic ★★ same type
TMPRSS15 c.2033-1G>A Likely pathogenic ★★ same type
TMPRSS15 c.2486+1G>A Likely pathogenic ★★ same type
TMPRSS15 p.Arg871Ter Pathogenic/Likely pathogenic ★★ same type
TMPRSS15 p.Ser712Ter Pathogenic ★★ same type
TMPRSS15 p.Ala491Thr Uncertain significance ★★ ⚠ same type
TMPRSS15 p.Ala744Val Uncertain significance ★★ ⚠ same type
TMPRSS15 p.Arg1000His 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/tmprss15-p-ser46phe (accessed [today's date]).

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