Is F5 p.Arg441Cys (c.1321C>T) pathogenic?

F5 p.Arg441Cys (c.1321C>T) is classified Conflicting classifications of pathogenicity in F5 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-29). AlphaMissense: ambiguous (0.3609); Very rare (popmax 0.00348%, nfe); Associated with factor V deficiency.

What condition is associated with F5 p.Arg441Cys (c.1321C>T)?

F5 p.Arg441Cys (c.1321C>T) is associated with factor V deficiency, thrombophilia due to activated protein C resistance (ClinVar).

How common is F5 p.Arg441Cys (c.1321C>T) in the general population?

F5 p.Arg441Cys (c.1321C>T) is very rare (popmax 0.00348%, nfe) (gnomAD).

What do computational predictors say about F5 p.Arg441Cys (c.1321C>T)?

AlphaMissense predicts ambiguous (score 0.3609) — an in-silico prediction, not a clinical call.

F5 p.Arg441Cys

c.1321C>T · rs747006175 · VCV627229

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00348%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

factor V deficiency

Computational evidence

Protein change
AlphaMissense	0.3609	ambiguous
REVEL	0.918	moderately pathogenic-leaning
SaProt	LLR -14.33	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.00099 · regional, not allelic
Overall
CADD	24.9	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 0.00348% European (non-Finnish) · 41/1,179,732 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00341% 55/1,613,590 alleles · very rare exomes 52/1,461,586 · genomes 3/152,004 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0187%	5,334
European (non-Finnish)grpmax	0.00348%	28,774
Remaining individualsnot grpmax-eligible	0.0016%	62,478
South Asian	0.0011%	91,078

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.Arg441Cys
Coding: c.1321C>T
MANE Select: NM_000130
dbSNP: rs747006175
Type: single nucleotide variant
Location: chr1:169550715 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 441: 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

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

Also linked: thrombophilia due to activated protein C resistance

Similar variants

F5 p.Arg441Gly Uncertain significance ⚠ same residue
F5 p.Arg441His 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

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-arg441cys (accessed [today's date]).

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