Is F5 p.Ala135= (c.405G>A) pathogenic?

F5 p.Ala135= (c.405G>A) is classified Benign/Likely benign in F5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 60.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with thrombophilia due to thrombin defect.

What condition is associated with F5 p.Ala135= (c.405G>A)?

F5 p.Ala135= (c.405G>A) is associated with thrombophilia due to thrombin defect, congenital factor V deficiency, Budd-Chiari syndrome (ClinVar).

F5 p.Ala135=

Q: How common is F5 p.Ala135= (c.405G>A) in the general population?

F5 p.Ala135= (c.405G>A) is common (popmax 60.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.405G>A · rs6029 · VCV255207

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 60.6%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

thrombophilia due to thrombin defect

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.42	acceptor gain · deltas
Pangolin	Δ0.31	gain · loss 0.07 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -3.5	GERP -3.7
Overall
CADD	17.26	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 60.6% East Asian · 27,139/44,796 alleles

Filtering AF 60% ClinGen BA1/BS1 input FAF95, joint · FAF99 59.7%

Overall 21% 338,337/1,612,154 alleles · common exomes 292,195/1,460,430 · genomes 46,142/151,724 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	60.6%	2
African / African-American	52.3%	2
Admixed American	27.4%	4
Finnishnot grpmax-eligible	25.7%	4
Remaining individualsnot grpmax-eligible	24.4%	4
Middle Eastern	21%	5
Ashkenazi Jewishnot grpmax-eligible	20.9%	5
South Asian	17.6%	6
European (non-Finnish)	17%	6
Amishnot grpmax-eligible	8.79%	11

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.Ala135=
Coding: c.405G>A
MANE Select: NM_000130
dbSNP: rs6029
Type: single nucleotide variant
Location: chr1:169560735 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 135: an α-helix; 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.Ala135Val Likely benign ★ 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-ala135 (accessed [today's date]).

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