Is F2RL3 p.Pro233Ser (c.697C>T) pathogenic?

F2RL3 p.Pro233Ser (c.697C>T) is classified Uncertain significance in F2RL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: ambiguous (0.3741); Very rare (popmax 0.00448%, eas).

How common is F2RL3 p.Pro233Ser (c.697C>T) in the general population?

F2RL3 p.Pro233Ser (c.697C>T) is very rare (popmax 0.00448%, eas) (gnomAD).

What do computational predictors say about F2RL3 p.Pro233Ser (c.697C>T)?

AlphaMissense predicts ambiguous (score 0.3741) — an in-silico prediction, not a clinical call.

F2RL3 p.Pro233Ser

c.697C>T · VCV3847023

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3741 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00448%, eas)

Computational evidence

Protein change
AlphaMissense	0.3741	ambiguous
REVEL	0.402	indeterminate
SaProt	LLR -7.77	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.7	GERP 0.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 1,428 bp · p 0.56 · regional, not allelic
Overall
CADD	24.9	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 0.00448% East Asian · 2/44,688 alleles

Filtering AF 0.000742% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.000564% 9/1,594,708 alleles · very rare exomes 8/1,442,492 · genomes 1/152,216 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00644%	15,516
East Asiangrpmax	0.00448%	22,344
Admixed American	0.00168%	59,414
South Asian	0.00111%	90,282
European (non-Finnish)	8.49e-05%	1,177,677

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: F2RL3
Protein: p.Pro233Ser
Coding: c.697C>T
MANE Select: NM_003950
Type: single nucleotide variant
Location: chr19:16890160 (GRCh38)
Gene constraint: LOEUF 1.746 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 80.67 · 3 PDB

Full F2RL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

F2RL3 p.Pro233Thr Uncertain significance ★ same residue
F2RL3 p.Ala120Thr Benign ★★ same type
F2RL3 p.Leu257= Benign ★★ same type
F2RL3 p.Tyr322= Benign ★★ same type
F2RL3 p.Ala128Val Uncertain significance ★ ⚠ same type
F2RL3 p.Ala186Gly Uncertain significance ★ ⚠ same type
F2RL3 p.Ala199Ser Uncertain significance ★ ⚠ same type
F2RL3 p.Ala200Val 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/f2rl3-p-pro233ser (accessed [today's date]).

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