Is PROS1 p.Ser321= (c.963C>T) pathogenic?

PROS1 p.Ser321= (c.963C>T) is classified Uncertain significance in PROS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). Very rare (popmax 0.0011%, sas); Associated with thrombophilia due to protein S deficiency, autosomal recessive.

What condition is associated with PROS1 p.Ser321= (c.963C>T)?

PROS1 p.Ser321= (c.963C>T) is associated with thrombophilia due to protein S deficiency, autosomal recessive (ClinVar).

How common is PROS1 p.Ser321= (c.963C>T) in the general population?

PROS1 p.Ser321= (c.963C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

PROS1 p.Ser321=

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.963C>T · rs569018785 · VCV2963858

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

thrombophilia due to protein S deficiency, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.26	donor loss, 2 bp away · masked 0 · deltas
Pangolin	Δ0.48	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Overall
CADD	19.01	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,802 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000188% 3/1,599,986 alleles · very rare exomes 2/1,447,802 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,802
European (non-Finnish)	0.000171%	583,710

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.Ser321=
Coding: c.963C>T
MANE Select: NM_000313
dbSNP: rs569018785
Type: single nucleotide variant
Location: chr3:93896578 (GRCh38)
Gene constraint: LOEUF 0.53 · pLI 0.75 (gnomAD)
Structure: AlphaFold pLDDT 83.06 · 3 PDB
Residue 321: the laminin g-like 1 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 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
PROS1 p.Arg451Ter 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-ser321 (accessed [today's date]).

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