Is F3 p.Arg176Trp (c.526C>T) pathogenic?

F3 p.Arg176Trp (c.526C>T) is classified Uncertain significance in F3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: ambiguous (0.3605); Very rare (popmax 0.0055%, sas).

How common is F3 p.Arg176Trp (c.526C>T) in the general population?

F3 p.Arg176Trp (c.526C>T) is very rare (popmax 0.0055%, sas) (gnomAD).

What do computational predictors say about F3 p.Arg176Trp (c.526C>T)?

AlphaMissense predicts ambiguous (score 0.3605) — an in-silico prediction, not a clinical call.

F3 p.Arg176Trp

c.526C>T · rs767150963 · VCV2242137

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3605 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0055%, sas)

Computational evidence

Protein change
AlphaMissense	0.3605	ambiguous
REVEL	0.538	indeterminate
SaProt	LLR -9.13	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Overall
CADD	31.0	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 0.0055% South Asian · 5/90,938 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.00093% 15/1,613,672 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0055%	18,188
African / African-American	0.00534%	18,722
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)	0.000339%	294,984

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.Arg176Trp
Coding: c.526C>T
MANE Select: NM_001843 · reported on NM_001993
dbSNP: rs767150963
Type: single nucleotide variant
Location: chr1:94533155 (GRCh38)
Structure: AlphaFold pLDDT 87.29 · 2 PDB
Residue 176: 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-arg176trp (accessed [today's date]).

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