Is FLRT3 p.Ala73Asp (c.218C>A) pathogenic?

FLRT3 p.Ala73Asp (c.218C>A) is classified Uncertain significance in FLRT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-09). AlphaMissense: ambiguous (0.5583); Very rare (popmax 0.00446%, eas).

How common is FLRT3 p.Ala73Asp (c.218C>A) in the general population?

FLRT3 p.Ala73Asp (c.218C>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about FLRT3 p.Ala73Asp (c.218C>A)?

AlphaMissense predicts ambiguous (score 0.5583) — an in-silico prediction, not a clinical call.

FLRT3 p.Ala73Asp

c.218C>A · rs755239011 · VCV3095709

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5583 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Computational evidence

Protein change
AlphaMissense	0.5583	ambiguous
REVEL	0.291	indeterminate
SaProt	LLR -6.01	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.5	GERP 2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,946 bp · p 4e-08 · regional, not allelic
Overall
CADD	25.1	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 0.00446% East Asian · 2/44,872 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00031% 5/1,613,738 alleles · very rare exomes 5/1,461,520 · genomes 0/152,218 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,827
East Asiangrpmax	0.00446%	22,436

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: FLRT3
Protein: p.Ala73Asp
Coding: c.218C>A
MANE Select: NM_198391
dbSNP: rs755239011
Type: single nucleotide variant
Location: chr20:14327289 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 74.57 · 3 PDB
Residue 73: an α-helix

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-ala73asp (accessed [today's date]).

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