Is F12 p.Pro488Ser (c.1462C>T) pathogenic?

F12 p.Pro488Ser (c.1462C>T) is classified Uncertain significance in F12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-29). AlphaMissense: ambiguous (0.3831); Absent from gnomAD v4.1; Associated with congenital factor XII deficiency.

What condition is associated with F12 p.Pro488Ser (c.1462C>T)?

F12 p.Pro488Ser (c.1462C>T) is associated with congenital factor XII deficiency (ClinVar).

How common is F12 p.Pro488Ser (c.1462C>T) in the general population?

F12 p.Pro488Ser (c.1462C>T) is absent from gnomAD v4.1 (gnomAD).

How is Congenital factor XII deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about F12 p.Pro488Ser (c.1462C>T)?

AlphaMissense predicts ambiguous (score 0.3831) — an in-silico prediction, not a clinical call.

F12 p.Pro488Ser

c.1462C>T · rs749774889 · VCV3065581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3831 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,599,318)

Conditions

congenital factor XII deficiency

Computational evidence

Protein change
AlphaMissense	0.3831	ambiguous
REVEL	0.548	indeterminate
SaProt	LLR -13.71	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,232 bp · p 0.39 · regional, not allelic
Overall
CADD	27.4	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

No allele count reported in gnomAD v4.1 (AN 1,599,318). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: F12
Protein: p.Pro488Ser
Coding: c.1462C>T
MANE Select: NM_000505
dbSNP: rs749774889
Type: single nucleotide variant
Location: chr5:177403323 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 488: an α-helix; the peptidase s1 domain

Full F12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Congenital factor XII deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

F12 p.Thr328Lys Pathogenic ★★ ⚠ same condition
F12 p.Gly360Val Uncertain significance ★★ ⚠ same condition
F12 p.Leu120His Uncertain significance ★★ ⚠ same condition
F12 c.398-12C>T Benign/Likely benign ★★ same condition
F12 c.-4T>C Benign/Likely benign ★★ same condition
F12 c.-8C>T Likely benign ★★ same condition
F12 p.Ala207Pro Benign/Likely benign ★★ same condition
F12 p.Ala252= Benign/Likely benign ★★ 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/f12-p-pro488ser (accessed [today's date]).

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