Is FLRT3 p.Leu109Val (c.325T>G) pathogenic?

FLRT3 p.Leu109Val (c.325T>G) is classified Uncertain significance in FLRT3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1973); Ultra-rare (popmax 0.088%, afr).

How common is FLRT3 p.Leu109Val (c.325T>G) in the general population?

FLRT3 p.Leu109Val (c.325T>G) is ultra-rare (popmax 0.088%, afr) (gnomAD).

What do computational predictors say about FLRT3 p.Leu109Val (c.325T>G)?

AlphaMissense predicts likely benign (score 0.1973) — an in-silico prediction, not a clinical call.

FLRT3 p.Leu109Val

c.325T>G · rs571028191 · VCV4526345

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1973 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.088%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1973	likely benign
REVEL	0.738	pathogenic-leaning
SaProt	LLR -10.40	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP -1.6, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,946 bp · p 4e-08 · regional, not allelic
Overall
CADD	23.2	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 0.088% African / African-American · 66/74,960 alleles

Filtering AF 0.071% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0648%

Overall 0.007% 113/1,613,618 alleles · ultra-rare exomes 68/1,461,448 · genomes 45/152,170 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.088%	1,136
Middle Eastern	0.0496%	2,017
Admixed American	0.0317%	3,156
Remaining individualsnot grpmax-eligible	0.0048%	20,826
European (non-Finnish)	0.00186%	53,624

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.Leu109Val
Coding: c.325T>G
MANE Select: NM_198391
dbSNP: rs571028191
Type: single nucleotide variant
Location: chr20:14327182 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 74.57 · 3 PDB
Residue 109: a β-strand

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.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
FLRT3 p.Ala377Thr Benign/Likely benign ★★ 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-leu109val (accessed [today's date]).

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