Is F5 p.Ala516Ser (c.1546G>T) pathogenic?

F5 p.Ala516Ser (c.1546G>T) is classified Uncertain significance in F5 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.1332); Absent from gnomAD v4.1; Associated with thrombophilia due to thrombin defect.

What condition is associated with F5 p.Ala516Ser (c.1546G>T)?

F5 p.Ala516Ser (c.1546G>T) is associated with thrombophilia due to thrombin defect, thrombophilia due to activated protein C resistance, Budd-Chiari syndrome (ClinVar).

How common is F5 p.Ala516Ser (c.1546G>T) in the general population?

F5 p.Ala516Ser (c.1546G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about F5 p.Ala516Ser (c.1546G>T)?

AlphaMissense predicts likely benign (score 0.1332) — an in-silico prediction, not a clinical call.

F5 p.Ala516Ser

c.1546G>T · rs916286148 · VCV874517

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1332 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

thrombophilia due to thrombin defect

Computational evidence

Protein change
AlphaMissense	0.1332	likely benign
REVEL	0.556	indeterminate
SaProt	LLR -4.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 0.054, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.00099 · regional, not allelic
Overall
CADD	23.4	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: F5
Protein: p.Ala516Ser
Coding: c.1546G>T
MANE Select: NM_000130
dbSNP: rs916286148
Type: single nucleotide variant
Location: chr1:169549866 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 516: a β-strand; 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 thrombin defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia due to activated protein C resistance Budd-Chiari syndrome factor V deficiency

Similar variants

F5 p.Ala516Thr Uncertain significance ★ ⚠ same residue
F5 c.1297-2A>G Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg1030Ter Pathogenic ★★ same condition
F5 p.Arg740Ter Pathogenic/Likely pathogenic ★★ same condition
F5 p.Tyr1730Cys Pathogenic/Likely pathogenic ★★ same condition
F5 c.-110C>A Uncertain significance ★★ same condition
F5 p.Ala38Thr Uncertain significance ★★ ⚠ same condition
F5 p.Arg1715Gln 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-ala516ser (accessed [today's date]).

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