Is F8 p.Pro1765Arg (c.5294C>G) pathogenic?

F8 p.Pro1765Arg (c.5294C>G) is classified Uncertain significance in F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1555); Very rare (popmax 0.000224%, nfe); Associated with Inborn genetic diseases.

What condition is associated with F8 p.Pro1765Arg (c.5294C>G)?

F8 p.Pro1765Arg (c.5294C>G) is associated with Inborn genetic diseases (ClinVar).

How common is F8 p.Pro1765Arg (c.5294C>G) in the general population?

F8 p.Pro1765Arg (c.5294C>G) is very rare (popmax 0.000224%, nfe) (gnomAD).

What do computational predictors say about F8 p.Pro1765Arg (c.5294C>G)?

AlphaMissense predicts likely benign (score 0.1555) — an in-silico prediction, not a clinical call.

F8 p.Pro1765Arg

c.5294C>G · VCV4839754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1555 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000224%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1555	likely benign
REVEL	0.424	indeterminate
SaProt	LLR -8.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 0.46, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 91 kb · p 1.5e-14 · regional, not allelic
Overall
CADD	21.2	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

Grpmax group 0.000224% European (non-Finnish) · 2/894,030 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000165% 2/1,209,778 alleles · very rare exomes 2/1,096,628 · genomes 0/113,150 · joint denominator

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: F8
Protein: p.Pro1765Arg
Coding: c.5294C>G
MANE Select: NM_000132
Type: single nucleotide variant
Location: chrX:154906499 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 1765: the f5/8 type a 3 domain; the plastocyanin-like 5 domain

Full F8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

F8 p.Pro1765Thr Uncertain significance ★ ⚠ same residue
F8 p.Tyr1699Phe Pathogenic ★★ ⚠ same condition
F8 p.Ala2108Val Uncertain significance ★★ ⚠ same condition
F8 p.Gln1049Lys Uncertain significance ★★ ⚠ same condition
F8 p.Gln1209Arg Uncertain significance ★★ ⚠ same condition
F8 p.Gly1729Trp Uncertain significance ★★ ⚠ same condition
F8 p.Leu13Phe Uncertain significance ★★ ⚠ same condition
F8 p.Ser1968Asn 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/f8-p-pro1765arg (accessed [today's date]).

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