Is F3 p.Ser174Arg (c.522C>G) pathogenic?

F3 p.Ser174Arg (c.522C>G) is classified Uncertain significance in F3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). AlphaMissense: ambiguous (0.5562); Rare (popmax 0.116%, mid).

How common is F3 p.Ser174Arg (c.522C>G) in the general population?

F3 p.Ser174Arg (c.522C>G) is rare (popmax 0.116%, mid) (gnomAD).

What do computational predictors say about F3 p.Ser174Arg (c.522C>G)?

AlphaMissense predicts ambiguous (score 0.5562) — an in-silico prediction, not a clinical call.

F3 p.Ser174Arg

c.522C>G · rs200192517 · VCV3091453

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5562 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5562	ambiguous
REVEL	0.157	moderately benign-leaning
SaProt	LLR -9.01	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP -0.32, phastCons 0.88
Overall
CADD	18.77	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 0.116% Middle Eastern · 7/6,060 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0444%

Overall 0.0123% 199/1,613,882 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.116%	866
African / African-American	0.064%	1,562
Admixed American	0.0467%	2,142
Remaining individualsnot grpmax-eligible	0.0272%	3,676
European (non-Finnish)	0.00831%	12,040
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598

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: F3
Protein: p.Ser174Arg
Coding: c.522C>G
MANE Select: NM_001843 · reported on NM_001993
dbSNP: rs200192517
Type: single nucleotide variant
Location: chr1:94533159 (GRCh38)
Structure: AlphaFold pLDDT 87.29 · 2 PDB
Residue 174: a disulfide bond; the ig-like c2-type 2 domain; a β-strand

Full F3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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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/f3-p-ser174arg (accessed [today's date]).

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