Is F5 p.Phe679Leu (c.2037C>G) pathogenic?

F5 p.Phe679Leu (c.2037C>G) is classified Conflicting classifications of pathogenicity in F5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.9834); Ultra-rare (popmax 0.0388%, nfe); Associated with thrombophilia due to thrombin defect.

What condition is associated with F5 p.Phe679Leu (c.2037C>G)?

F5 p.Phe679Leu (c.2037C>G) is associated with thrombophilia due to thrombin defect, congenital factor V deficiency, Budd-Chiari syndrome (ClinVar).

How common is F5 p.Phe679Leu (c.2037C>G) in the general population?

F5 p.Phe679Leu (c.2037C>G) is ultra-rare (popmax 0.0388%, nfe) (gnomAD).

What do computational predictors say about F5 p.Phe679Leu (c.2037C>G)?

AlphaMissense predicts likely pathogenic (score 0.9834) — an in-silico prediction, not a clinical call.

F5 p.Phe679Leu

c.2037C>G · rs374118662 · VCV875334

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9834 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0388%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to thrombin defect

Computational evidence

Protein change
AlphaMissense	0.9834	likely pathogenic · top 1% in F5
REVEL	0.711	pathogenic-leaning
SaProt	LLR -9.19	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.00099 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0388% European (non-Finnish) · 458/1,179,940 alleles

Filtering AF 0.0359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0347%

Overall 0.0307% 495/1,613,848 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0576%	1,735
European (non-Finnish)grpmax	0.0388%	2,576
African / African-American	0.00134%	74,892

Remaining individuals 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: F5
Protein: p.Phe679Leu
Coding: c.2037C>G
MANE Select: NM_000130
dbSNP: rs374118662
Type: single nucleotide variant
Location: chr1:169543053 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 679: the plastocyanin-like 4 domain; a disulfide bond; a β-strand; the f5/8 type a 2 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 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
F5 p.Asp96His 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-phe679leu (accessed [today's date]).

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