Is F12 p.Phe518Ser (c.1553T>C) pathogenic?

F12 p.Phe518Ser (c.1553T>C) is classified Uncertain significance in F12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-31). AlphaMissense: likely benign (0.3296); Very rare (popmax 0.00415%, nfe); Associated with Inborn genetic diseases.

What condition is associated with F12 p.Phe518Ser (c.1553T>C)?

F12 p.Phe518Ser (c.1553T>C) is associated with Inborn genetic diseases (ClinVar).

How common is F12 p.Phe518Ser (c.1553T>C) in the general population?

F12 p.Phe518Ser (c.1553T>C) is very rare (popmax 0.00415%, nfe) (gnomAD).

What do computational predictors say about F12 p.Phe518Ser (c.1553T>C)?

AlphaMissense predicts likely benign (score 0.3296) — an in-silico prediction, not a clinical call.

F12 p.Phe518Ser

c.1553T>C · rs752701059 · VCV3091401

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3296 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3296	likely benign
REVEL	0.46	indeterminate
SaProt	LLR -5.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.27, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,232 bp · p 0.39 · regional, not allelic
Overall
CADD	23.2	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 0.00415% European (non-Finnish) · 49/1,180,004 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00323% 52/1,611,996 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00415%	24,082
African / African-American	0.00401%	24,966

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.Phe518Ser
Coding: c.1553T>C
MANE Select: NM_000505
dbSNP: rs752701059
Type: single nucleotide variant
Location: chr5:177402677 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 518: a disulfide bond; the peptidase s1 domain

Full F12 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

F12 p.Ala452Thr Uncertain significance ★★ ⚠ same condition
F12 p.Arg55Trp Uncertain significance ★★ ⚠ same condition
F12 p.Glu288Lys Uncertain significance ★★ same condition
F12 p.Gly360Val Uncertain significance ★★ ⚠ same condition
F12 p.Leu120His Uncertain significance ★★ ⚠ same condition
F12 p.Ser308Phe Uncertain significance ★★ ⚠ same condition
F12 p.Ser479Pro Uncertain significance ★★ ⚠ same condition
F12 p.Ser99Thr 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/f12-p-phe518ser (accessed [today's date]).

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