Is PROS1 p.Pro416= (c.1248G>A) pathogenic?

PROS1 p.Pro416= (c.1248G>A) is classified Likely benign in PROS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-27). Rare (popmax 0.148%, afr); Associated with thrombophilia due to protein S deficiency, autosomal recessive.

What condition is associated with PROS1 p.Pro416= (c.1248G>A)?

PROS1 p.Pro416= (c.1248G>A) is associated with thrombophilia due to protein S deficiency, autosomal recessive (ClinVar).

How common is PROS1 p.Pro416= (c.1248G>A) in the general population?

PROS1 p.Pro416= (c.1248G>A) is rare (popmax 0.148%, afr) (gnomAD).

PROS1 p.Pro416=

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.1248G>A · rs148869673 · VCV699801

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.148%, afr)

Conditions

thrombophilia due to protein S deficiency, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -1.4, phastCons 1
Overall
CADD	13.65	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.148% African / African-American · 111/75,002 alleles

Filtering AF 0.126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.117%

Overall 0.0128% 206/1,613,806 alleles · rare exomes 131/1,461,572 · genomes 75/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.148%	676
Remaining individualsnot grpmax-eligible	0.0304%	3,289
South Asian	0.0285%	3,503
Admixed American	0.00667%	15,003
European (non-Finnish)	0.0039%	25,649

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.Pro416=
Coding: c.1248G>A
MANE Select: NM_000313
dbSNP: rs148869673
Type: single nucleotide variant
Location: chr3:93886411 (GRCh38)
Gene constraint: LOEUF 0.53 · pLI 0.75 (gnomAD)
Structure: AlphaFold pLDDT 83.06 · 3 PDB
Residue 416: 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 p.Pro416Leu 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
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-pro416 (accessed [today's date]).

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