Is FLRT3 p.Glu460Asp (c.1380A>C) pathogenic?

FLRT3 p.Glu460Asp (c.1380A>C) is classified Benign in FLRT3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0607); Common (popmax 12.2%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about FLRT3 p.Glu460Asp (c.1380A>C)?

AlphaMissense predicts likely benign (score 0.0607) — an in-silico prediction, not a clinical call.

FLRT3 p.Glu460Asp

Q: How common is FLRT3 p.Glu460Asp (c.1380A>C) in the general population?

FLRT3 p.Glu460Asp (c.1380A>C) is common (popmax 12.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1380A>C · rs35253731 · VCV1259515

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0607 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 12.2%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0607	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -4.09	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 0.53	GERP -2.1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,946 bp · p 4e-08 · regional, not allelic
Overall
CADD	8.948	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 12.2% African / African-American · 9,151/75,000 alleles

Filtering AF 12% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.9%

Overall 2.98% 48,041/1,613,846 alleles · common exomes 40,122/1,461,608 · genomes 7,919/152,238 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.2%	8
Amishnot grpmax-eligible	4.82%	21
Remaining individualsnot grpmax-eligible	3.41%	29
Ashkenazi Jewishnot grpmax-eligible	3.23%	31
Finnishnot grpmax-eligible	3%	33
European (non-Finnish)	2.56%	39
Middle Eastern	2.41%	41
East Asian	2.11%	47
Admixed American	1.73%	58
South Asian	1.64%	61

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.Glu460Asp
Coding: c.1380A>C
MANE Select: NM_198391
dbSNP: rs35253731
Type: single nucleotide variant
Location: chr20:14326127 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 74.57 · 3 PDB
Residue 460: the fibronectin type-iii domain; a UniProt-annotated variant site (in)

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-glu460asp (accessed [today's date]).

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