Is FBL p.Arg21Pro (c.62G>C) pathogenic?

FBL p.Arg21Pro (c.62G>C) is classified Uncertain significance in FBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: ambiguous (0.5541); Very rare (popmax 0.0023%, sas).

How common is FBL p.Arg21Pro (c.62G>C) in the general population?

FBL p.Arg21Pro (c.62G>C) is very rare (popmax 0.0023%, sas) (gnomAD).

What do computational predictors say about FBL p.Arg21Pro (c.62G>C)?

AlphaMissense predicts ambiguous (score 0.5541) — an in-silico prediction, not a clinical call.

FBL p.Arg21Pro

c.62G>C · VCV4255366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5541 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5541	ambiguous
REVEL	0.161	moderately benign-leaning
SaProt	LLR -13.03	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 12 kb · p 2.6e-05 · regional, not allelic
Overall
CADD	23.0	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 0.0023% South Asian · 2/86,866 alleles

Filtering AF 0.000382% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000143%

Overall 0.000381% 6/1,576,210 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0023%	43,433
Admixed American	0.00188%	53,246
Remaining individualsnot grpmax-eligible	0.00164%	61,098
European (non-Finnish)	0.000172%	580,582

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: FBL
Protein: p.Arg21Pro
Coding: c.62G>C
MANE Select: NM_001436
Type: single nucleotide variant
Location: chr19:39840736 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.11 · 12 PDB
Residue 21: the 'disordered' region; a modified residue (asymmetric dimethylarginine)

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

Similar variants

FBL p.Arg21Cys Uncertain significance ★ ⚠ same residue
FBL p.Arg21His Uncertain significance ★ ⚠ same residue
FBL p.Gly13= Benign ★★ same type
FBL p.Ala161Thr Uncertain significance ★ ⚠ same type
FBL p.Arg195His Uncertain significance ★ ⚠ same type
FBL p.Arg198His Uncertain significance ★ ⚠ same type
FBL p.Arg218Gln Uncertain significance ★ ⚠ same type
FBL p.Arg224His Uncertain significance ★ ⚠ same type

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/fbl-p-arg21pro (accessed [today's date]).

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