Is F5 p.His175Arg (c.524A>G) pathogenic?

F5 p.His175Arg (c.524A>G) is classified Conflicting classifications of pathogenicity in F5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1684); Rare (popmax 0.176%, eas); Associated with factor V deficiency.

What condition is associated with F5 p.His175Arg (c.524A>G)?

F5 p.His175Arg (c.524A>G) is associated with factor V deficiency, thrombophilia due to thrombin defect, congenital factor V deficiency (ClinVar).

How common is F5 p.His175Arg (c.524A>G) in the general population?

F5 p.His175Arg (c.524A>G) is rare (popmax 0.176%, eas) (gnomAD).

What do computational predictors say about F5 p.His175Arg (c.524A>G)?

AlphaMissense predicts likely benign (score 0.1684) — an in-silico prediction, not a clinical call.

F5 p.His175Arg

c.524A>G · rs201510575 · VCV293639

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1684 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.176%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

factor V deficiency

Computational evidence

Protein change
AlphaMissense	0.1684	likely benign
REVEL	0.887	moderately pathogenic-leaning
SaProt	LLR -4.81	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -0.69, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.00099 · regional, not allelic
Overall
CADD	22.1	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 0.176% East Asian · 79/44,840 alleles

Filtering AF 0.145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.133%

Overall 0.0169% 272/1,613,772 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.176%	568
South Asian	0.113%	884
Remaining individualsnot grpmax-eligible	0.109%	919
African / African-American	0.016%	6,249
Admixed American	0.00167%	59,984
European (non-Finnish)	0.000763%	131,090

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.His175Arg
Coding: c.524A>G
MANE Select: NM_000130
dbSNP: rs201510575
Type: single nucleotide variant
Location: chr1:169560616 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 175: a disulfide bond; 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 congenital factor V deficiency Budd-Chiari syndrome

Similar variants

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
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-his175arg (accessed [today's date]).

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