Is F5 p.Val94Ala (c.281T>C) pathogenic?

F5 p.Val94Ala (c.281T>C) is classified Uncertain significance in F5 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.1861); Ultra-rare (popmax 0.0136%, nfe); Associated with factor V deficiency.

What condition is associated with F5 p.Val94Ala (c.281T>C)?

F5 p.Val94Ala (c.281T>C) is associated with factor V deficiency, thrombophilia due to thrombin defect, thrombophilia due to activated protein C resistance (ClinVar).

How common is F5 p.Val94Ala (c.281T>C) in the general population?

F5 p.Val94Ala (c.281T>C) is ultra-rare (popmax 0.0136%, nfe) (gnomAD).

What do computational predictors say about F5 p.Val94Ala (c.281T>C)?

AlphaMissense predicts likely benign (score 0.1861) — an in-silico prediction, not a clinical call.

F5 p.Val94Ala

c.281T>C · rs751093518 · VCV874767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1861 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

factor V deficiency

Computational evidence

Protein change
AlphaMissense	0.1861	likely benign
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -10.86	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.00099 · regional, not allelic
Overall
CADD	23.7	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 0.0136% European (non-Finnish) · 161/1,179,630 alleles

Filtering AF 0.0119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0113%

Overall 0.0101% 163/1,613,220 alleles · ultra-rare exomes 160/1,461,050 · genomes 3/152,170 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0136%	7,327
Admixed American	0.00167%	59,932
Remaining individualsnot grpmax-eligible	0.0016%	62,434

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.Val94Ala
Coding: c.281T>C
MANE Select: NM_000130
dbSNP: rs751093518
Type: single nucleotide variant
Location: chr1:169572313 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 94: the f5/8 type a 1 domain; the plastocyanin-like 1 domain

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

Disease context

factor V deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia due to thrombin defect thrombophilia due to activated protein C resistance Budd-Chiari syndrome

Similar variants

F5 p.Val94= Likely benign ★★ 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-val94ala (accessed [today's date]).

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