Is PROS1 p.Pro20Arg (c.59C>G) pathogenic?

PROS1 p.Pro20Arg (c.59C>G) is classified Uncertain significance in PROS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-11). AlphaMissense: likely benign (0.1832); Absent from gnomAD v4.1; Associated with thrombophilia due to protein S deficiency, autosomal recessive.

What condition is associated with PROS1 p.Pro20Arg (c.59C>G)?

PROS1 p.Pro20Arg (c.59C>G) is associated with thrombophilia due to protein S deficiency, autosomal recessive (ClinVar).

How common is PROS1 p.Pro20Arg (c.59C>G) in the general population?

PROS1 p.Pro20Arg (c.59C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROS1 p.Pro20Arg (c.59C>G)?

AlphaMissense predicts likely benign (score 0.1832) — an in-silico prediction, not a clinical call.

PROS1 p.Pro20Arg

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.59C>G · rs1709918238 · VCV1721146

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1832 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

thrombophilia due to protein S deficiency, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.1832	likely benign
REVEL	0.429	indeterminate
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.85, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 100 kb · p 4.7e-06 · regional, not allelic
Overall
CADD	19.39	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: PROS1
Protein: p.Pro20Arg
Coding: c.59C>G
MANE Select: NM_000313
dbSNP: rs1709918238
Type: single nucleotide variant
Location: chr3:93973691 (GRCh38)
Gene constraint: LOEUF 0.53 · pLI 0.75 (gnomAD)
Structure: AlphaFold pLDDT 83.06 · 3 PDB

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.Pro20= Likely benign ★ 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
PROS1 p.Arg355His 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-pro20arg (accessed [today's date]).

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