Is TMPRSS15 p.Ser264Pro (c.790T>C) pathogenic?

TMPRSS15 p.Ser264Pro (c.790T>C) is classified Uncertain significance in TMPRSS15 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-04). AlphaMissense: likely pathogenic (0.7566); Ultra-rare (popmax 0.0944%, afr).

How common is TMPRSS15 p.Ser264Pro (c.790T>C) in the general population?

TMPRSS15 p.Ser264Pro (c.790T>C) is ultra-rare (popmax 0.0944%, afr) (gnomAD).

What do computational predictors say about TMPRSS15 p.Ser264Pro (c.790T>C)?

AlphaMissense predicts likely pathogenic (score 0.7566) — an in-silico prediction, not a clinical call.

TMPRSS15 p.Ser264Pro

c.790T>C · rs201269085 · VCV2153812

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7566 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0944%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7566	likely pathogenic
REVEL	0.231	benign-leaning
SaProt	LLR -11.79	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 4.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 134 kb · p 0.043 · regional, not allelic
Overall
CADD	21.2	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 0.0944% African / African-American · 69/73,098 alleles

Filtering AF 0.0764% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.07%

Overall 0.00818% 124/1,515,702 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0944%	1,059
Admixed American	0.0337%	2,971
Remaining individualsnot grpmax-eligible	0.00851%	11,750
European (non-Finnish)	0.00275%	36,427

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: TMPRSS15
Protein: p.Ser264Pro
Coding: c.790T>C
MANE Select: NM_002772
dbSNP: rs201269085
Type: single nucleotide variant
Location: chr21:18359847 (GRCh38)
Gene constraint: LOEUF 1.12 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.03 · 14 PDB
Residue 264: the cub 1 domain

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-ser264pro (accessed [today's date]).

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