Is F12 p.Ala379Val (c.1136C>T) pathogenic?

F12 p.Ala379Val (c.1136C>T) is classified Uncertain significance in F12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: ambiguous (0.5559); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with F12 p.Ala379Val (c.1136C>T)?

F12 p.Ala379Val (c.1136C>T) is associated with Inborn genetic diseases (ClinVar).

How common is F12 p.Ala379Val (c.1136C>T) in the general population?

F12 p.Ala379Val (c.1136C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about F12 p.Ala379Val (c.1136C>T)?

AlphaMissense predicts ambiguous (score 0.5559) — an in-silico prediction, not a clinical call.

F12 p.Ala379Val

c.1136C>T · VCV4619010

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5559 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5559	ambiguous
REVEL	0.346	indeterminate
SaProt	LLR -7.74	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,232 bp · p 0.39 · regional, not allelic
Overall
CADD	27.5	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 0.00167% Admixed American · 1/59,858 alleles

Overall 0.000138% 2/1,450,354 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,858
European (non-Finnish)	8.48e-05%	1,179,376

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: F12
Protein: p.Ala379Val
Coding: c.1136C>T
MANE Select: NM_000505
Type: single nucleotide variant
Location: chr5:177403973 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 379: the peptidase s1 domain

Full F12 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

F12 p.Ala452Thr Uncertain significance ★★ ⚠ same condition
F12 p.Arg55Trp Uncertain significance ★★ ⚠ same condition
F12 p.Glu288Lys Uncertain significance ★★ same condition
F12 p.Gly360Val Uncertain significance ★★ ⚠ same condition
F12 p.Leu120His Uncertain significance ★★ ⚠ same condition
F12 p.Phe518Ser Uncertain significance ★★ ⚠ same condition
F12 p.Ser308Phe Uncertain significance ★★ ⚠ same condition
F12 p.Ser479Pro 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/f12-p-ala379val (accessed [today's date]).

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