Is F2 p.Ser331Leu (c.992C>T) pathogenic?

F2 p.Ser331Leu (c.992C>T) is classified Conflicting classifications of pathogenicity in F2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-11). AlphaMissense: likely benign (0.0591); Ultra-rare (popmax 0.0165%, mid); Associated with thrombophilia due to thrombin defect.

What condition is associated with F2 p.Ser331Leu (c.992C>T)?

F2 p.Ser331Leu (c.992C>T) is associated with thrombophilia due to thrombin defect, congenital prothrombin deficiency (ClinVar).

How common is F2 p.Ser331Leu (c.992C>T) in the general population?

F2 p.Ser331Leu (c.992C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about F2 p.Ser331Leu (c.992C>T)?

AlphaMissense predicts likely benign (score 0.0591) — an in-silico prediction, not a clinical call.

F2 p.Ser331Leu

c.992C>T · rs200812621 · VCV304815

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0591 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to thrombin defect

Computational evidence

Protein change
AlphaMissense	0.0591	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -5.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.53 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.2	GERP -3
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	4.68	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0072%

Overall 0.00192% 31/1,614,120 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.016%	6,254
East Asian	0.0156%	6,409
Remaining individualsnot grpmax-eligible	0.0016%	62,500
European (non-Finnish)	0.000847%	117,999

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.Ser331Leu
Coding: c.992C>T
MANE Select: NM_000506
dbSNP: rs200812621
Type: single nucleotide variant
Location: chr11:46726615 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 331: an α-helix

Full F2 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 prothrombin deficiency

Similar variants

F2 p.Ser331= 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-ser331leu (accessed [today's date]).

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