Is F12 p.Leu18Phe (c.52C>T) pathogenic?

F12 p.Leu18Phe (c.52C>T) is classified Uncertain significance in F12 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-10). AlphaMissense: likely benign (0.0734); Rare (popmax 0.113%, afr).

How common is F12 p.Leu18Phe (c.52C>T) in the general population?

F12 p.Leu18Phe (c.52C>T) is rare (popmax 0.113%, afr) (gnomAD).

What do computational predictors say about F12 p.Leu18Phe (c.52C>T)?

AlphaMissense predicts likely benign (score 0.0734) — an in-silico prediction, not a clinical call.

F12 p.Leu18Phe

c.52C>T · rs138423738 · VCV2849386

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0734 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.113%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0734	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -7.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -4.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,232 bp · p 0.39 · regional, not allelic
Overall
CADD	15.03	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.113% African / African-American · 85/75,002 alleles

Filtering AF 0.0938% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0867%

Overall 0.00626% 101/1,614,054 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.113%	882
Middle Eastern	0.033%	3,031
Admixed American	0.00667%	15,002
Remaining individualsnot grpmax-eligible	0.0064%	15,626
South Asian	0.00329%	30,359
European (non-Finnish)	0.000254%	393,329

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: F12
Protein: p.Leu18Phe
Coding: c.52C>T
MANE Select: NM_000505
dbSNP: rs138423738
Type: single nucleotide variant
Location: chr5:177409476 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB

Full F12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

F12 p.Glu193Ter Pathogenic/Likely pathogenic ★★ same type
F12 p.Thr328Lys Pathogenic ★★ ⚠ same type
F12 c.57+4A>G Uncertain significance ★★ same type
F12 p.Ala452Thr Uncertain significance ★★ ⚠ same type
F12 p.Arg55Trp Uncertain significance ★★ ⚠ same type
F12 p.Asp283= Uncertain significance ★★ same type
F12 p.Glu288Lys Uncertain significance ★★ same type
F12 p.Gly360Val Uncertain significance ★★ ⚠ same type

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/f12-p-leu18phe (accessed [today's date]).

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