Is PROS1 p.Ser596Phe (c.1787C>T) pathogenic?

PROS1 p.Ser596Phe (c.1787C>T) is classified Uncertain significance in PROS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-30). AlphaMissense: likely benign (0.1097); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PROS1 p.Ser596Phe (c.1787C>T)?

PROS1 p.Ser596Phe (c.1787C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PROS1 p.Ser596Phe (c.1787C>T) in the general population?

PROS1 p.Ser596Phe (c.1787C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROS1 p.Ser596Phe (c.1787C>T)?

AlphaMissense predicts likely benign (score 0.1097) — an in-silico prediction, not a clinical call.

PROS1 p.Ser596Phe

c.1787C>T · VCV3425658

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1097 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1097	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -7.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.93	GERP -0.65, phastCons 0.9
Regional constraint	o/e 0.84	unconstrained · MANE · 100 kb · p 4.7e-06 · regional, not allelic
Overall
CADD	13.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PROS1
Protein: p.Ser596Phe
Coding: c.1787C>T
MANE Select: NM_000313
Type: single nucleotide variant
Location: chr3:93877049 (GRCh38)
Gene constraint: LOEUF 0.53 · pLI 0.75 (gnomAD)
Structure: AlphaFold pLDDT 83.06 · 3 PDB
Residue 596: the laminin g-like 2 domain

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.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
PROS1 p.Asn177Asp 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-ser596phe (accessed [today's date]).

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