Is FLRT3 p.Ile452Val (c.1354A>G) pathogenic?

FLRT3 p.Ile452Val (c.1354A>G) is classified Uncertain significance in FLRT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-20). AlphaMissense: likely benign (0.1936); Very rare (popmax 0.00334%, amr).

How common is FLRT3 p.Ile452Val (c.1354A>G) in the general population?

FLRT3 p.Ile452Val (c.1354A>G) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about FLRT3 p.Ile452Val (c.1354A>G)?

AlphaMissense predicts likely benign (score 0.1936) — an in-silico prediction, not a clinical call.

FLRT3 p.Ile452Val

c.1354A>G · rs1393315241 · VCV1678235

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1936	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,946 bp · p 4e-08 · regional, not allelic
Overall
CADD	18.94	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 0.00334% Admixed American · 2/59,956 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000372% 6/1,613,770 alleles · very rare exomes 4/1,461,592 · genomes 2/152,178 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,978
East Asian	0.00223%	44,882
Remaining individualsnot grpmax-eligible	0.0016%	62,468
African / African-American	0.00133%	74,916
European (non-Finnish)	8.48e-05%	1,179,878

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: FLRT3
Protein: p.Ile452Val
Coding: c.1354A>G
MANE Select: NM_198391
dbSNP: rs1393315241
Type: single nucleotide variant
Location: chr20:14326153 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 74.57 · 3 PDB
Residue 452: the fibronectin type-iii domain; a UniProt-annotated variant site (found in a renal cell carcinoma case; somatic mutation)

Full FLRT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FLRT3 p.Arg163Cys Uncertain significance ★★ ⚠ same type
FLRT3 p.Leu109Val Uncertain significance ★★ ⚠ same type
FLRT3 p.Ser25Pro Uncertain significance ★★ ⚠ same type
FLRT3 p.Ser284Arg Uncertain significance ★★ ⚠ same type
FLRT3 p.Ser33Pro Uncertain significance ★★ ⚠ same type
FLRT3 p.Thr199Ser Uncertain significance ★★ ⚠ same type
FLRT3 p.Thr419Ser Uncertain significance ★★ ⚠ same type
FLRT3 p.Trp381Arg 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/flrt3-p-ile452val (accessed [today's date]).

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