Is F12 p.Ala159Thr (c.475G>A) pathogenic?

F12 p.Ala159Thr (c.475G>A) is classified Uncertain significance in F12 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-03). AlphaMissense: likely benign (0.0815); Ultra-rare (popmax 0.0922%, sas); Associated with Inborn genetic diseases.

What condition is associated with F12 p.Ala159Thr (c.475G>A)?

F12 p.Ala159Thr (c.475G>A) is associated with Inborn genetic diseases (ClinVar).

How common is F12 p.Ala159Thr (c.475G>A) in the general population?

F12 p.Ala159Thr (c.475G>A) is ultra-rare (popmax 0.0922%, sas) (gnomAD).

What do computational predictors say about F12 p.Ala159Thr (c.475G>A)?

AlphaMissense predicts likely benign (score 0.0815) — an in-silico prediction, not a clinical call.

F12 p.Ala159Thr

c.475G>A · rs536792519 · VCV2409724

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0815 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0922%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0815	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.55	GERP 1.2, phastCons 0.98
Regional constraint	o/e 0.97	unconstrained · MANE · 7,232 bp · p 0.39 · regional, not allelic
Overall
CADD	14.18	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 0.0922% South Asian · 84/91,090 alleles

Filtering AF 0.0763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0704%

Overall 0.00552% 89/1,613,762 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0922%	1,084
Remaining individualsnot grpmax-eligible	0.008%	12,500

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.Ala159Thr
Coding: c.475G>A
MANE Select: NM_000505
dbSNP: rs536792519
Type: single nucleotide variant
Location: chr5:177405108 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 159: a disulfide bond; the fibronectin type-i domain; a β-strand

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-ala159thr (accessed [today's date]).

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