Is F9 p.Pro324His (c.971C>A) pathogenic?

F9 p.Pro324His (c.971C>A) is classified Uncertain significance in F9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-08). AlphaMissense: likely benign (0.2318); Very rare (popmax 0.000447%, nfe).

How common is F9 p.Pro324His (c.971C>A) in the general population?

F9 p.Pro324His (c.971C>A) is very rare (popmax 0.000447%, nfe) (gnomAD).

What do computational predictors say about F9 p.Pro324His (c.971C>A)?

AlphaMissense predicts likely benign (score 0.2318) — an in-silico prediction, not a clinical call.

F9 p.Pro324His

c.971C>A · rs1225527981 · VCV2627159

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2318 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000447%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2318	likely benign
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -11.76	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 5.1, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic
Overall
CADD	24.2	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 0.000447% European (non-Finnish) · 4/895,474 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.000364% 4/1,098,118 alleles · very rare

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: F9
Protein: p.Pro324His
Coding: c.971C>A
MANE Select: NM_000133
dbSNP: rs1225527981
Type: single nucleotide variant
Location: chrX:139561656 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 324: an α-helix; a disulfide bond; the peptidase s1 domain

Full F9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

F9 p.Pro324= Likely benign ★ same residue
F9 p.Pro324fs Pathogenic ★★★ same residue
F9 c.520+13A>G Pathogenic ★★★ same type
F9 c.88+1G>A Pathogenic ★★★ same type
F9 c.88+5G>T Likely pathogenic ★★★ same type
F9 p.Ala279Thr Pathogenic ★★★ ⚠ same type
F9 p.Ala337Pro Likely pathogenic ★★★ ⚠ same type
F9 p.Ala337Thr Pathogenic ★★★ ⚠ same type

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/f9-p-pro324his (accessed [today's date]).

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