Is F5 p.Ser1469Pro (c.4405T>C) pathogenic?

F5 p.Ser1469Pro (c.4405T>C) is classified Conflicting classifications of pathogenicity in F5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.086); Rare (popmax 0.237%, afr); Associated with thrombophilia due to thrombin defect.

What condition is associated with F5 p.Ser1469Pro (c.4405T>C)?

F5 p.Ser1469Pro (c.4405T>C) is associated with thrombophilia due to thrombin defect, congenital factor V deficiency, Budd-Chiari syndrome (ClinVar).

How common is F5 p.Ser1469Pro (c.4405T>C) in the general population?

F5 p.Ser1469Pro (c.4405T>C) is rare (popmax 0.237%, afr) (gnomAD).

What do computational predictors say about F5 p.Ser1469Pro (c.4405T>C)?

AlphaMissense predicts likely benign (score 0.086) — an in-silico prediction, not a clinical call.

F5 p.Ser1469Pro

c.4405T>C · rs144262027 · VCV293595

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.086 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.237%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

thrombophilia due to thrombin defect

Computational evidence

Protein change
AlphaMissense	0.086	likely benign
REVEL	0.342	indeterminate
SaProt	LLR -6.36	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 0.5, phastCons 0.16
Regional constraint	o/e 1.08	unconstrained · MANE · 679 bp · p 0.18 · regional, not allelic
Overall
CADD	12.78	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 0.237% African / African-American · 178/75,046 alleles

Filtering AF 0.209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.198%

Overall 0.0136% 219/1,614,094 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.237%	422
Remaining individualsnot grpmax-eligible	0.0176%	5,683
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,401
Admixed American	0.00667%	15,001
European (non-Finnish)	0.00178%	56,189
South Asian	0.0011%	91,082

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.Ser1469Pro
Coding: c.4405T>C
MANE Select: NM_000130
dbSNP: rs144262027
Type: single nucleotide variant
Location: chr1:169540685 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 1469: 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

thrombophilia due to thrombin defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital factor V deficiency Budd-Chiari syndrome factor V deficiency

Similar variants

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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
F5 p.Asp96His 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-ser1469pro (accessed [today's date]).

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