Is PROS1 p.Pro667= (c.2001A>G) pathogenic?

PROS1 p.Pro667= (c.2001A>G) is classified Benign in PROS1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 57.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with thrombophilia due to protein S deficiency, autosomal recessive.

What condition is associated with PROS1 p.Pro667= (c.2001A>G)?

PROS1 p.Pro667= (c.2001A>G) is associated with thrombophilia due to protein S deficiency, autosomal recessive, thrombophilia due to protein S deficiency, autosomal dominant (ClinVar).

PROS1 p.Pro667=

Q: How common is PROS1 p.Pro667= (c.2001A>G) in the general population?

PROS1 p.Pro667= (c.2001A>G) is common (popmax 57.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.2001A>G · rs6123 · VCV255811

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 57.8%, eas) — too common for a highly-penetrant pathogenic allele

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 -1.8	GERP -0.72
Overall
CADD	3.731	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 57.8% East Asian · 25,883/44,788 alleles

Filtering AF 57.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 57%

Overall 40.5% 653,048/1,613,070 alleles · common exomes 600,048/1,461,048 · genomes 53,000/152,022 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	57.8%	2
South Asian	50.6%	2
Amishnot grpmax-eligible	48.7%	2
Admixed American	47.6%	2
Finnishnot grpmax-eligible	44.6%	2
European (non-Finnish)	40.4%	2
Remaining individualsnot grpmax-eligible	39.4%	3
Middle Eastern	37.9%	3
Ashkenazi Jewishnot grpmax-eligible	32.2%	3
African / African-American	14.8%	7

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.Pro667=
Coding: c.2001A>G
MANE Select: NM_000313
dbSNP: rs6123
Type: single nucleotide variant
Location: chr3:93874275 (GRCh38)
Gene constraint: LOEUF 0.53 · pLI 0.75 (gnomAD)
Structure: AlphaFold pLDDT 83.06 · 3 PDB
Residue 667: 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

Also linked: thrombophilia due to protein S deficiency, autosomal dominant

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

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PROS1 p.Pro667Leu Conflicting classifications of pathogenicity ★ 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-pro667 (accessed [today's date]).

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