Is PROS1 p.Ser28Pro (c.82T>C) pathogenic?

PROS1 p.Ser28Pro (c.82T>C) is classified Uncertain significance in PROS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-15). AlphaMissense: likely benign (0.1644); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with PROS1 p.Ser28Pro (c.82T>C)?

PROS1 p.Ser28Pro (c.82T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PROS1 p.Ser28Pro (c.82T>C) in the general population?

PROS1 p.Ser28Pro (c.82T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PROS1 p.Ser28Pro (c.82T>C)?

AlphaMissense predicts likely benign (score 0.1644) — an in-silico prediction, not a clinical call.

PROS1 p.Ser28Pro

c.82T>C · rs776526548 · VCV2207705

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1644 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1644	likely benign
REVEL	0.63	indeterminate
SaProt	LLR -7.93	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 -1.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 100 kb · p 4.7e-06 · regional, not allelic
Overall
CADD	21.2	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

Grpmax group 0.00167% Admixed American · 1/60,002 alleles

Overall 0.000124% 2/1,614,056 alleles · very rare exomes 2/1,461,728 · genomes 0/152,328 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,002
European (non-Finnish)	8.47e-05%	1,179,997

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.Ser28Pro
Coding: c.82T>C
MANE Select: NM_000313
dbSNP: rs776526548
Type: single nucleotide variant
Location: chr3:93927402 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROS1 p.Ser28Ter Pathogenic ★ same residue
PROS1 p.Glu576Val Uncertain significance ★★ ⚠ same condition
PROS1 p.Val37Phe Uncertain significance ★★ ⚠ same condition
PROS1 p.Ala307Glu Uncertain significance ★ ⚠ same condition
PROS1 p.Ala403Val Uncertain significance ★ ⚠ same condition
PROS1 p.Ala610Pro Uncertain significance ★ ⚠ same condition
PROS1 p.Ala68Val Uncertain significance ★ ⚠ same condition
PROS1 p.Arg7Leu Uncertain significance ★ ⚠ 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-ser28pro (accessed [today's date]).

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