Is PROS1 p.Arg515Pro (c.1544G>C) pathogenic?

PROS1 p.Arg515Pro (c.1544G>C) is classified Likely pathogenic in PROS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-12). AlphaMissense: likely pathogenic (0.9784); Absent from gnomAD v4.1; Associated with thrombophilia due to protein S deficiency, autosomal recessive.

What condition is associated with PROS1 p.Arg515Pro (c.1544G>C)?

PROS1 p.Arg515Pro (c.1544G>C) is associated with thrombophilia due to protein S deficiency, autosomal recessive (ClinVar).

How common is PROS1 p.Arg515Pro (c.1544G>C) in the general population?

PROS1 p.Arg515Pro (c.1544G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROS1 p.Arg515Pro (c.1544G>C)?

AlphaMissense predicts likely pathogenic (score 0.9784) — an in-silico prediction, not a clinical call.

PROS1 p.Arg515Pro

Q: How is Severe hereditary thrombophilia due to congenital protein S deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1544G>C · rs769700380 · VCV2203405

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9784 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to protein S deficiency, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9784	likely pathogenic ✓ concordant with ClinVar · top 2% in PROS1
REVEL	0.701	pathogenic-leaning
SaProt	LLR -12.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 100 kb · p 4.7e-06 · regional, not allelic
Overall
CADD	22.9	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

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: PROS1
Protein: p.Arg515Pro
Coding: c.1544G>C
MANE Select: NM_000313
dbSNP: rs769700380
Type: single nucleotide variant
Location: chr3:93879263 (GRCh38)
Gene constraint: LOEUF 0.53 · pLI 0.75 (gnomAD)
Structure: AlphaFold pLDDT 83.06 · 3 PDB
Residue 515: a UniProt-annotated variant site (in thph5; secretion of the mutant markedly decreased compared with that of the wild-type; intracellular degradation and impaired secretion of the mutant); a UniProt-annotated variant site (in thph5); the laminin g-like 2 domain

Full PROS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

thrombophilia due to protein S deficiency, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe hereditary thrombophilia due to congenital protein S deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PROS1 p.Arg515His Uncertain significance ★★ ⚠ same residue
PROS1 p.Arg515Cys Likely pathogenic ★ same residue
PROS1 c.1155+5G>A Pathogenic/Likely pathogenic ★★ same condition
PROS1 c.1870+1G>C Pathogenic ★★ same condition
PROS1 c.235-2A>G Pathogenic/Likely pathogenic ★★ same condition
PROS1 c.601+1G>A Pathogenic/Likely pathogenic ★★ same condition
PROS1 c.77-1G>C Pathogenic ★★ same condition
PROS1 p.Arg355Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition

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/pros1-p-arg515pro (accessed [today's date]).

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