Is F2RL3 p.Phe254Ile (c.760T>A) pathogenic?

F2RL3 p.Phe254Ile (c.760T>A) is classified Uncertain significance in F2RL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-26). AlphaMissense: likely benign (0.223); Rare (popmax 0.153%, mid).

How common is F2RL3 p.Phe254Ile (c.760T>A) in the general population?

F2RL3 p.Phe254Ile (c.760T>A) is rare (popmax 0.153%, mid) (gnomAD).

What do computational predictors say about F2RL3 p.Phe254Ile (c.760T>A)?

AlphaMissense predicts likely benign (score 0.223) — an in-silico prediction, not a clinical call.

F2RL3 p.Phe254Ile

c.760T>A · rs867168857 · VCV2273747

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.223 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.153%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.223	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -9.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.36	GERP -4.1, phastCons 0.93
Regional constraint	o/e 1.02	unconstrained · MANE · 1,428 bp · p 0.56 · regional, not allelic
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.153% Middle Eastern · 9/5,866 alleles

Filtering AF 0.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0598%

Overall 0.000632% 10/1,582,304 alleles · rare exomes 10/1,430,068 · genomes 0/152,236 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.153%	652
European (non-Finnish)	8.54e-05%	1,170,744

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.Phe254Ile
Coding: c.760T>A
MANE Select: NM_003950
dbSNP: rs867168857
Type: single nucleotide variant
Location: chr19:16890223 (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.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
F2RL3 p.Ala208Ser 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-phe254ile (accessed [today's date]).

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