Is F12 p.Pro342Leu (c.1025C>T) pathogenic?

F12 p.Pro342Leu (c.1025C>T) is classified Conflicting classifications of pathogenicity in F12 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-02-01). AlphaMissense: likely benign (0.0696); Rare (popmax 0.121%, nfe); Associated with hereditary angioedema type 3.

What condition is associated with F12 p.Pro342Leu (c.1025C>T)?

F12 p.Pro342Leu (c.1025C>T) is associated with hereditary angioedema type 3, congenital factor XII deficiency (ClinVar).

How common is F12 p.Pro342Leu (c.1025C>T) in the general population?

F12 p.Pro342Leu (c.1025C>T) is rare (popmax 0.121%, nfe) (gnomAD).

What do computational predictors say about F12 p.Pro342Leu (c.1025C>T)?

AlphaMissense predicts likely benign (score 0.0696) — an in-silico prediction, not a clinical call.

F12 p.Pro342Leu

c.1025C>T · rs2230939 · VCV352993

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0696 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.121%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary angioedema type 3

Computational evidence

Protein change
AlphaMissense	0.0696	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -7.80	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 -0.8	GERP -3.8
Regional constraint	o/e 0.97	unconstrained · MANE · 7,232 bp · p 0.39 · regional, not allelic
Overall
CADD	0.322	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 0.121% European (non-Finnish) · 1,424/1,178,594 alleles

Filtering AF 0.116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.113%

Overall 0.0992% 1,589/1,602,298 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.121%	828
Remaining individualsnot grpmax-eligible	0.109%	915
Admixed American	0.0739%	1,354
Finnishnot grpmax-eligible	0.0453%	2,206
Middle Eastern	0.0331%	3,022
African / African-American	0.02%	5,002
South Asian	0.00994%	10,065
Ashkenazi Jewishnot grpmax-eligible	0.00679%	14,728

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.Pro342Leu
Coding: c.1025C>T
MANE Select: NM_000505
dbSNP: rs2230939
Type: single nucleotide variant
Location: chr5:177404084 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 342: the 'disordered' region; a UniProt-annotated variant site (in)

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.Pro342Arg Uncertain significance ★ ⚠ same residue
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

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-pro342leu (accessed [today's date]).

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