Is F5 p.Ala37= (c.111T>A) pathogenic?

F5 p.Ala37= (c.111T>A) is classified Conflicting classifications of pathogenicity in F5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-02-12). Ultra-rare (popmax 0.0439%, sas); Associated with thrombophilia due to thrombin defect.

What condition is associated with F5 p.Ala37= (c.111T>A)?

F5 p.Ala37= (c.111T>A) is associated with thrombophilia due to thrombin defect, congenital factor V deficiency, Budd-Chiari syndrome (ClinVar).

How common is F5 p.Ala37= (c.111T>A) in the general population?

F5 p.Ala37= (c.111T>A) is ultra-rare (popmax 0.0439%, sas) (gnomAD).

F5 p.Ala37=

c.111T>A · rs537081933 · VCV293643

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0439%, sas)

Conditions

thrombophilia due to thrombin defect

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3	GERP -3.8
Overall
CADD	2.768	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0439% South Asian · 40/91,078 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.00297% 48/1,614,196 alleles · ultra-rare exomes 44/1,461,866 · genomes 4/152,330 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0439%	2,277
Remaining individualsnot grpmax-eligible	0.0128%	7,814

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: F5
Protein: p.Ala37=
Coding: c.111T>A
MANE Select: NM_000130
dbSNP: rs537081933
Type: single nucleotide variant
Location: chr1:169586276 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 37: a β-strand; the f5/8 type a 1 domain; the plastocyanin-like 1 domain

Full F5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

thrombophilia due to thrombin defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital factor V deficiency Budd-Chiari syndrome factor V deficiency

Similar variants

F5 p.Ala37Pro Uncertain significance ★ ⚠ same residue
F5 c.1297-2A>G Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg1030Ter Pathogenic ★★ same condition
F5 p.Arg146Ter Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg1621Ter Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg1634Ter Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg2102His Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg740Ter Pathogenic/Likely pathogenic ★★ 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/f5-p-ala37 (accessed [today's date]).

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