Is F10 p.Pro422Ala (c.1264C>G) pathogenic?

F10 p.Pro422Ala (c.1264C>G) is classified Uncertain significance in F10 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-28). AlphaMissense: likely pathogenic (0.9125); Very rare (popmax 0.00133%, afr); Associated with F10-related disorder.

What condition is associated with F10 p.Pro422Ala (c.1264C>G)?

F10 p.Pro422Ala (c.1264C>G) is associated with F10-related disorder (ClinVar).

How common is F10 p.Pro422Ala (c.1264C>G) in the general population?

F10 p.Pro422Ala (c.1264C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about F10 p.Pro422Ala (c.1264C>G)?

AlphaMissense predicts likely pathogenic (score 0.9125) — an in-silico prediction, not a clinical call.

F10 p.Pro422Ala

c.1264C>G · VCV3348717

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9125 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

F10-related disorder

Computational evidence

Protein change
AlphaMissense	0.9125	likely pathogenic
REVEL	0.875	moderately pathogenic-leaning
SaProt	LLR -12.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.8, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 10 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/74,942 alleles

Overall 6.2e-05% 1/1,613,126 alleles · very rare exomes 0/1,460,916 · genomes 1/152,210 · 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: F10
Protein: p.Pro422Ala
Coding: c.1264C>G
MANE Select: NM_000504
Type: single nucleotide variant
Location: chr13:113149314 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.47 · 192 PDB
Residue 422: the peptidase s1 domain; a β-strand

Full F10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

F10-related disorder

Similar variants

F10 p.Arg426Cys Likely pathogenic ★ ⚠ same condition
F10 c.70+1G>A Likely pathogenic same condition
F10 p.Gly289Arg Pathogenic same condition
F10 p.Gly259= Likely benign same condition
F10 p.Ala12fs Likely pathogenic ★ same condition
F10 p.Glu54Gly Likely pathogenic ★★ same type
F10 p.Gly21Arg Pathogenic ★★ ⚠ same type
F10 p.Gly363Ser Likely 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/f10-p-pro422ala (accessed [today's date]).

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