Is FLRT3 p.Ala531Val (c.1592C>T) pathogenic?

FLRT3 p.Ala531Val (c.1592C>T) is classified Uncertain significance in FLRT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-23). AlphaMissense: likely benign (0.2139); Ultra-rare (popmax 0.0373%, sas).

How common is FLRT3 p.Ala531Val (c.1592C>T) in the general population?

FLRT3 p.Ala531Val (c.1592C>T) is ultra-rare (popmax 0.0373%, sas) (gnomAD).

What do computational predictors say about FLRT3 p.Ala531Val (c.1592C>T)?

AlphaMissense predicts likely benign (score 0.2139) — an in-silico prediction, not a clinical call.

FLRT3 p.Ala531Val

c.1592C>T · VCV4690844

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2139 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2139	likely benign
REVEL	0.364	indeterminate
SaProt	LLR -8.34	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,946 bp · p 4e-08 · regional, not allelic
Overall
CADD	24.3	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 0.0373% South Asian · 34/91,084 alleles

Filtering AF 0.0274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.024%

Overall 0.00229% 37/1,613,830 alleles · ultra-rare exomes 35/1,461,678 · genomes 2/152,152 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0373%	2,679
Admixed American	0.005%	19,990

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.Ala531Val
Coding: c.1592C>T
MANE Select: NM_198391
Type: single nucleotide variant
Location: chr20:14325915 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 74.57 · 3 PDB

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-ala531val (accessed [today's date]).

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