Is F12 p.Ser308Tyr (c.923C>A) pathogenic?

F12 p.Ser308Tyr (c.923C>A) is classified Conflicting classifications of pathogenicity in F12 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-09). AlphaMissense: likely benign (0.1025); Rare (popmax 0.187%, afr); Associated with Inborn genetic diseases.

What condition is associated with F12 p.Ser308Tyr (c.923C>A)?

F12 p.Ser308Tyr (c.923C>A) is associated with Inborn genetic diseases (ClinVar).

How common is F12 p.Ser308Tyr (c.923C>A) in the general population?

F12 p.Ser308Tyr (c.923C>A) is rare (popmax 0.187%, afr) (gnomAD).

What do computational predictors say about F12 p.Ser308Tyr (c.923C>A)?

AlphaMissense predicts likely benign (score 0.1025) — an in-silico prediction, not a clinical call.

F12 p.Ser308Tyr

c.923C>A · rs139263608 · VCV1510718

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1025 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.187%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1025	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -9.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.52 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.74	GERP -2.8
Regional constraint	o/e 0.97	unconstrained · MANE · 7,232 bp · p 0.39 · regional, not allelic
Overall
CADD	12.66	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 0.187% African / African-American · 140/74,712 alleles

Filtering AF 0.162% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.152%

Overall 0.0093% 149/1,601,610 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.187%	534
Middle Eastern	0.0166%	6,010
Remaining individualsnot grpmax-eligible	0.00808%	12,374
European (non-Finnish)	0.000256%	391,250

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.Ser308Tyr
Coding: c.923C>A
MANE Select: NM_000505
dbSNP: rs139263608
Type: single nucleotide variant
Location: chr5:177404291 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 308: the 'disordered' region

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.Ser308Phe Uncertain significance ★★ ⚠ same residue
F12 p.Ser308Thr Likely benign ★ same residue
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.Phe518Ser 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-ser308tyr (accessed [today's date]).

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