Is F5 p.Arg428Ser (c.1284A>T) pathogenic?

F5 p.Arg428Ser (c.1284A>T) is classified Uncertain significance in F5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). AlphaMissense: likely pathogenic (0.8683); Absent from gnomAD v4.1; Associated with thrombophilia due to activated protein C resistance.

What condition is associated with F5 p.Arg428Ser (c.1284A>T)?

F5 p.Arg428Ser (c.1284A>T) is associated with thrombophilia due to activated protein C resistance (ClinVar).

How common is F5 p.Arg428Ser (c.1284A>T) in the general population?

F5 p.Arg428Ser (c.1284A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about F5 p.Arg428Ser (c.1284A>T)?

AlphaMissense predicts likely pathogenic (score 0.8683) — an in-silico prediction, not a clinical call.

F5 p.Arg428Ser

c.1284A>T · VCV3377663

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8683 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to activated protein C resistance

Computational evidence

Protein change
AlphaMissense	0.8683	likely pathogenic · top 8% in F5
REVEL	0.68	pathogenic-leaning
SaProt	LLR -6.16	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.69	donor gain · deltas
Pangolin	Δ0.50	gain · loss 0.28 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.3	GERP -1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.00099 · regional, not allelic
Overall
CADD	26.4	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

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: F5
Protein: p.Arg428Ser
Coding: c.1284A>T
MANE Select: NM_000130
Type: single nucleotide variant
Location: chr1:169552569 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 428: the f5/8 type a 2 domain; the plastocyanin-like 3 domain

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

Disease context

thrombophilia due to activated protein C resistance — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

F5 p.Arg428Gly Uncertain significance ★ same residue
F5 p.Arg1030Ter Pathogenic ★★ same condition
F5 p.Ala38Thr Uncertain significance ★★ ⚠ same condition
F5 p.Arg1715Gln Uncertain significance ★★ ⚠ same condition
F5 p.Arg376Ser Uncertain significance ★★ ⚠ same condition
F5 p.His1845Arg Uncertain significance ★★ ⚠ same condition
F5 p.Ile2136Thr Uncertain significance ★★ ⚠ same condition
F5 p.Thr1978Ile 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/f5-p-arg428ser (accessed [today's date]).

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