Is F12 p.Leu140Val (c.418C>G) pathogenic?

F12 p.Leu140Val (c.418C>G) is classified Conflicting classifications of pathogenicity in F12 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1439); Rare (popmax 0.346%, nfe); Associated with hereditary angioedema type 3.

What condition is associated with F12 p.Leu140Val (c.418C>G)?

F12 p.Leu140Val (c.418C>G) is associated with hereditary angioedema type 3, congenital factor XII deficiency (ClinVar).

How common is F12 p.Leu140Val (c.418C>G) in the general population?

F12 p.Leu140Val (c.418C>G) is rare (popmax 0.346%, nfe) (gnomAD).

What do computational predictors say about F12 p.Leu140Val (c.418C>G)?

AlphaMissense predicts likely benign (score 0.1439) — an in-silico prediction, not a clinical call.

F12 p.Leu140Val

c.418C>G · rs35515200 · VCV353001

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1439 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.346%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary angioedema type 3

Computational evidence

Protein change
AlphaMissense	0.1439	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -6.90	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 3.1	GERP -4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,232 bp · p 0.39 · regional, not allelic
Overall
CADD	19.72	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 0.346% European (non-Finnish) · 4,086/1,180,030 alleles

Filtering AF 0.337% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.334%

Overall 0.292% 4,720/1,614,000 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.346%	289
Remaining individualsnot grpmax-eligible	0.317%	316
Admixed American	0.316%	316
Finnishnot grpmax-eligible	0.213%	469
Middle Eastern	0.099%	1,010
Ashkenazi Jewishnot grpmax-eligible	0.0777%	1,287
African / African-American	0.0666%	1,502
South Asian	0.034%	2,938

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.Leu140Val
Coding: c.418C>G
MANE Select: NM_000505
dbSNP: rs35515200
Type: single nucleotide variant
Location: chr5:177405165 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 140: a disulfide bond; the fibronectin type-i domain; a turn

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

Disease context

hereditary angioedema type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital factor XII deficiency

Similar variants

F12 p.Thr328Lys Pathogenic ★★ ⚠ same condition
F12 p.Gly360Val Uncertain significance ★★ ⚠ same condition
F12 p.Leu120His Uncertain significance ★★ ⚠ same condition
F12 c.1019-28T>C Benign ★★ same condition
F12 c.1251-9C>T Benign/Likely benign ★★ same condition
F12 c.1681-7G>A Benign/Likely benign ★★ same condition
F12 c.398-12C>T Benign/Likely benign ★★ same condition
F12 c.-4T>C Benign/Likely benign ★★ 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/f12-p-leu140val (accessed [today's date]).

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