Is F5 p.Arg341Cys (c.1021C>T) pathogenic?

F5 p.Arg341Cys (c.1021C>T) is classified Conflicting classifications of pathogenicity in F5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-08-14). AlphaMissense: ambiguous (0.4799); Very rare (popmax 0.00267%, afr); Associated with Budd-Chiari syndrome.

What condition is associated with F5 p.Arg341Cys (c.1021C>T)?

F5 p.Arg341Cys (c.1021C>T) is associated with Budd-Chiari syndrome, thrombophilia due to thrombin defect, congenital factor V deficiency (ClinVar).

How common is F5 p.Arg341Cys (c.1021C>T) in the general population?

F5 p.Arg341Cys (c.1021C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Budd-Chiari syndrome inherited?

Typically Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about F5 p.Arg341Cys (c.1021C>T)?

AlphaMissense predicts ambiguous (score 0.4799) — an in-silico prediction, not a clinical call.

F5 p.Arg341Cys

c.1021C>T · rs200532195 · VCV874623

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4799 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Budd-Chiari syndrome

Computational evidence

Protein change
AlphaMissense	0.4799	ambiguous
REVEL	0.408	indeterminate
SaProt	LLR -10.45	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.2, phastCons 0.93
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.00099 · regional, not allelic
Overall
CADD	21.2	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 0.00267% African / African-American · 2/74,978 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.0329% 531/1,613,982 alleles · very rare exomes 424/1,461,830 · genomes 107/152,152 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.772%	130
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
African / African-Americangrpmax	0.00267%	37,489
European (non-Finnish)	0.00178%	56,189

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg341Cys
Coding: c.1021C>T
MANE Select: NM_000130
dbSNP: rs200532195
Type: single nucleotide variant
Location: chr1:169555279 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 341: a turn

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

Disease context

Budd-Chiari syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia due to thrombin defect congenital factor V deficiency factor V deficiency

For Budd-Chiari syndrome (Orphanet):

Inheritance: Multigenic/multifactorial
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

F5 p.Arg341His Uncertain significance ★ ⚠ same residue
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

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-arg341cys (accessed [today's date]).

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