Is F2 p.His605= (c.1815T>C) pathogenic?

F2 p.His605= (c.1815T>C) is classified Conflicting classifications of pathogenicity in F2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-11). Very rare (popmax 0.00534%, nfe); Associated with congenital prothrombin deficiency.

What condition is associated with F2 p.His605= (c.1815T>C)?

F2 p.His605= (c.1815T>C) is associated with congenital prothrombin deficiency, thrombophilia due to thrombin defect (ClinVar).

How common is F2 p.His605= (c.1815T>C) in the general population?

F2 p.His605= (c.1815T>C) is very rare (popmax 0.00534%, nfe) (gnomAD).

How is Congenital factor II deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

F2 p.His605=

c.1815T>C · rs368442575 · VCV304822

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, nfe)

Conditions

congenital prothrombin deficiency

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 -11	GERP -4.2
Overall
CADD	0.269	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% European (non-Finnish) · 63/1,179,962 alleles

Filtering AF 0.00426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.00434% 70/1,613,944 alleles · very rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.11%	912
European (non-Finnish)grpmax	0.00534%	18,730
Remaining individualsnot grpmax-eligible	0.0048%	20,826
Admixed American	0.00333%	29,993
African / African-American	0.00133%	74,918

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His605=
Coding: c.1815T>C
MANE Select: NM_000506
dbSNP: rs368442575
Type: single nucleotide variant
Location: chr11:46739354 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 605: the peptidase s1 domain; a β-strand

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

Disease context

congenital prothrombin deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia due to thrombin defect

For Congenital factor II deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

F2 p.His605fs Conflicting classifications of pathogenicity ★ 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-his605 (accessed [today's date]).

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