Is PROS1 p.Arg90Pro (c.269G>C) pathogenic?

PROS1 p.Arg90Pro (c.269G>C) is classified Uncertain significance in PROS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-02). AlphaMissense: ambiguous (0.4101); Very rare (popmax 8.49e-05%, nfe); Associated with thrombophilia due to protein S deficiency, autosomal recessive.

What condition is associated with PROS1 p.Arg90Pro (c.269G>C)?

PROS1 p.Arg90Pro (c.269G>C) is associated with thrombophilia due to protein S deficiency, autosomal recessive (ClinVar).

How common is PROS1 p.Arg90Pro (c.269G>C) in the general population?

PROS1 p.Arg90Pro (c.269G>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about PROS1 p.Arg90Pro (c.269G>C)?

AlphaMissense predicts ambiguous (score 0.4101) — an in-silico prediction, not a clinical call.

PROS1 p.Arg90Pro

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.269G>C · rs200886866 · VCV937023

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

thrombophilia due to protein S deficiency, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.4101	ambiguous
REVEL	0.624	indeterminate
SaProt	LLR -11.30	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 0.87, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 100 kb · p 4.7e-06 · regional, not allelic
Overall
CADD	22.5	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 8.49e-05% European (non-Finnish) · 1/1,178,298 alleles

Overall 6.21e-05% 1/1,611,528 alleles · very rare exomes 1/1,459,488 · genomes 0/152,040 · joint denominator

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: PROS1
Protein: p.Arg90Pro
Coding: c.269G>C
MANE Select: NM_000313
dbSNP: rs200886866
Type: single nucleotide variant
Location: chr3:93910696 (GRCh38)
Gene constraint: LOEUF 0.53 · pLI 0.75 (gnomAD)
Structure: AlphaFold pLDDT 83.06 · 3 PDB
Residue 90: the 'thrombin-sensitive' region; a UniProt-annotated variant site (in thph5; produces around 50% of pros1 levels compared to wild-type; has impaired secretion; intracellular degradation of unsecreted material is found); a UniProt-annotated variant site (in thph5)

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.Arg90Cys Uncertain significance ★★ ⚠ same residue
PROS1 p.Arg90His Uncertain significance ★ ⚠ 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-arg90pro (accessed [today's date]).

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