Is F2 p.Leu56Pro (c.167T>C) pathogenic?

F2 p.Leu56Pro (c.167T>C) is classified Uncertain significance in F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-02). AlphaMissense: likely pathogenic (0.7629); Very rare (popmax 0.00597%, nfe); Associated with Inborn genetic diseases.

What condition is associated with F2 p.Leu56Pro (c.167T>C)?

F2 p.Leu56Pro (c.167T>C) is associated with Inborn genetic diseases (ClinVar).

How common is F2 p.Leu56Pro (c.167T>C) in the general population?

F2 p.Leu56Pro (c.167T>C) is very rare (popmax 0.00597%, nfe) (gnomAD).

What do computational predictors say about F2 p.Leu56Pro (c.167T>C)?

AlphaMissense predicts likely pathogenic (score 0.7629) — an in-silico prediction, not a clinical call.

F2 p.Leu56Pro

c.167T>C · rs757486222 · VCV1777888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00597%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7629	likely pathogenic
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -13.75	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00597% European (non-Finnish) · 70/1,172,886 alleles

Filtering AF 0.00481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00441%

Overall 0.00445% 71/1,597,258 alleles · very rare exomes 69/1,445,066 · genomes 2/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00597%	16,756
African / African-American	0.00134%	74,690

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.Leu56Pro
Coding: c.167T>C
MANE Select: NM_000506
dbSNP: rs757486222
Type: single nucleotide variant
Location: chr11:46719789 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 56: the gla domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

F2 p.Leu56= Likely benign ★ same residue
F2 p.Ala490Thr Uncertain significance ★★ ⚠ same condition
F2 p.Arg217Gln Uncertain significance ★★ ⚠ same condition
F2 p.Arg224Cys Uncertain significance ★★ ⚠ same condition
F2 p.Arg35Trp Uncertain significance ★★ ⚠ same condition
F2 p.Ile438Thr Uncertain significance ★★ ⚠ same condition
F2 p.Pro471Thr Uncertain significance ★★ ⚠ same condition
F2 p.Thr488Met 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-leu56pro (accessed [today's date]).

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