Is F5 p.Pro1404Ser (c.4210C>T) pathogenic?

F5 p.Pro1404Ser (c.4210C>T) is classified Benign/Likely benign in F5 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0961); Common (popmax 17.6%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Budd-Chiari syndrome.

What condition is associated with F5 p.Pro1404Ser (c.4210C>T)?

F5 p.Pro1404Ser (c.4210C>T) is associated with Budd-Chiari syndrome, thrombophilia due to thrombin defect, congenital factor V deficiency (ClinVar).

How is Budd-Chiari syndrome inherited?

Typically Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about F5 p.Pro1404Ser (c.4210C>T)?

AlphaMissense predicts likely benign (score 0.0961) — an in-silico prediction, not a clinical call.

F5 p.Pro1404Ser

Q: How common is F5 p.Pro1404Ser (c.4210C>T) in the general population?

F5 p.Pro1404Ser (c.4210C>T) is common (popmax 17.6%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4210C>T · rs9332608 · VCV293599

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0961 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 17.6%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Budd-Chiari syndrome

Computational evidence

Protein change
AlphaMissense	0.0961	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -7.65	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 -0.83	GERP -2.5
Regional constraint	o/e 1.08	unconstrained · MANE · 679 bp · p 0.18 · regional, not allelic
Overall
CADD	1.505	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 17.6% Admixed American · 10,503/59,816 alleles

Filtering AF 17.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 17.2%

Overall 5% 80,662/1,613,180 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	17.6%	6
East Asian	14.2%	7
South Asian	9.69%	10
Ashkenazi Jewishnot grpmax-eligible	6.95%	14
Middle Eastern	6.26%	16
Remaining individualsnot grpmax-eligible	5.52%	18
Finnishnot grpmax-eligible	4.15%	24
European (non-Finnish)	3.73%	27
African / African-American	3.25%	31
Amishnot grpmax-eligible	2.63%	38

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: F5
Protein: p.Pro1404Ser
Coding: c.4210C>T
MANE Select: NM_000130
dbSNP: rs9332608
Type: single nucleotide variant
Location: chr1:169540880 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 1404: a UniProt-annotated variant site (in); the 'b' region; the '35 x 9 aa approximate tandem repeats of [tnp]-l-s-p-d-l-s-q-t' region

Full F5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Budd-Chiari syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia due to thrombin defect congenital factor V deficiency factor V deficiency

For Budd-Chiari syndrome (Orphanet):

Inheritance: Multigenic/multifactorial
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

F5 p.Pro1404fs Pathogenic ★ same residue
F5 c.1297-2A>G Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg1030Ter Pathogenic ★★ same condition
F5 p.Arg146Ter Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg1621Ter Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg1634Ter Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg2102His Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg740Ter Pathogenic/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/f5-p-pro1404ser (accessed [today's date]).

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