Is F2 p.Ala236Thr (c.706G>A) pathogenic?

F2 p.Ala236Thr (c.706G>A) is classified Uncertain significance in F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-16). AlphaMissense: likely benign (0.1358); Ultra-rare (popmax 0.0495%, mid); Associated with pregnancy loss, recurrent, susceptibility to, 2.

What condition is associated with F2 p.Ala236Thr (c.706G>A)?

F2 p.Ala236Thr (c.706G>A) is associated with pregnancy loss, recurrent, susceptibility to, 2, thrombophilia due to thrombin defect, congenital prothrombin deficiency (ClinVar).

How common is F2 p.Ala236Thr (c.706G>A) in the general population?

F2 p.Ala236Thr (c.706G>A) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about F2 p.Ala236Thr (c.706G>A)?

AlphaMissense predicts likely benign (score 0.1358) — an in-silico prediction, not a clinical call.

F2 p.Ala236Thr

c.706G>A · rs148020569 · VCV3891636

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1358 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pregnancy loss, recurrent, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.1358	likely benign
REVEL	0.235	benign-leaning
SaProt	LLR -8.34	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 0.22	GERP -2.9, phastCons 0.93
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	9.393	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 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.00812% 131/1,613,952 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,278
Remaining individualsnot grpmax-eligible	0.0144%	6,944
European (non-Finnish)	0.00839%	11,919
Admixed American	0.00833%	12,006
African / African-American	0.00266%	37,531

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: F2
Protein: p.Ala236Thr
Coding: c.706G>A
MANE Select: NM_000506
dbSNP: rs148020569
Type: single nucleotide variant
Location: chr11:46726005 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 236: an α-helix; a disulfide bond; the kringle 2 domain

Full F2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pregnancy loss, recurrent, susceptibility to, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia due to thrombin defect congenital prothrombin deficiency ischemic stroke

Similar variants

F2 p.Ala236= Likely benign ★ same residue
F2 p.Arg461Trp Pathogenic/Likely pathogenic ★★ same condition
F2 p.Arg500Gln Pathogenic ★★ ⚠ same condition
F2 p.Arg581Cys Pathogenic/Likely pathogenic ★★ same condition
F2 p.Arg596Gln Pathogenic ★★ ⚠ same condition
F2 p.Gln387Ter Pathogenic/Likely pathogenic ★★ same condition
F2 c.559+5G>A Uncertain significance ★★ same condition
F2 p.Ala17Ser 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/f2-p-ala236thr (accessed [today's date]).

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