Is PROS1 p.Arg2Ser (c.6G>T) pathogenic?

PROS1 p.Arg2Ser (c.6G>T) is classified Uncertain significance in PROS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). AlphaMissense: ambiguous (0.5209); Very rare (popmax 0.0011%, sas).

How common is PROS1 p.Arg2Ser (c.6G>T) in the general population?

PROS1 p.Arg2Ser (c.6G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PROS1 p.Arg2Ser (c.6G>T)?

AlphaMissense predicts ambiguous (score 0.5209) — an in-silico prediction, not a clinical call.

PROS1 p.Arg2Ser

c.6G>T · VCV3379481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5209 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Computational evidence

Protein change
AlphaMissense	0.5209	ambiguous
REVEL	0.636	indeterminate
SaProt	LLR -7.12	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -0.022, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 100 kb · p 4.7e-06 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,970 alleles

Overall 0.000124% 2/1,612,832 alleles · very rare exomes 2/1,460,520 · genomes 0/152,312 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,970
European (non-Finnish)	8.48e-05%	1,179,468

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.Arg2Ser
Coding: c.6G>T
MANE Select: NM_000313
Type: single nucleotide variant
Location: chr3:93973744 (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

Similar variants

PROS1 p.Arg2Lys Uncertain significance ★ ⚠ same residue
PROS1 c.1155+5G>A Pathogenic/Likely pathogenic ★★ same type
PROS1 c.1870+1G>C Pathogenic ★★ same type
PROS1 c.235-2A>G Pathogenic/Likely pathogenic ★★ same type
PROS1 c.601+1G>A Pathogenic/Likely pathogenic ★★ same type
PROS1 c.77-1G>C Pathogenic ★★ same type
PROS1 c.-168C>T Likely pathogenic ★★ same type
PROS1 p.Arg355Cys Pathogenic/Likely pathogenic ★★ ⚠ same type

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-arg2ser (accessed [today's date]).

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