Is FLRT3 p.Met333Ile (c.999G>A) pathogenic?

FLRT3 p.Met333Ile (c.999G>A) is classified Uncertain significance in FLRT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-04). AlphaMissense: likely pathogenic (0.8618); Absent from gnomAD v4.1; Associated with hypogonadotropic hypogonadism 21 with or without anosmia.

What condition is associated with FLRT3 p.Met333Ile (c.999G>A)?

FLRT3 p.Met333Ile (c.999G>A) is associated with hypogonadotropic hypogonadism 21 with or without anosmia (ClinVar).

How common is FLRT3 p.Met333Ile (c.999G>A) in the general population?

FLRT3 p.Met333Ile (c.999G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FLRT3 p.Met333Ile (c.999G>A)?

AlphaMissense predicts likely pathogenic (score 0.8618) — an in-silico prediction, not a clinical call.

FLRT3 p.Met333Ile

c.999G>A · rs2514830526 · VCV1710063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8618 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypogonadotropic hypogonadism 21 with or without anosmia

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.8618	likely pathogenic
REVEL	0.285	benign-leaning
SaProt	LLR -3.97	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,946 bp · p 4e-08 · regional, not allelic
Overall
CADD	23.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FLRT3
Protein: p.Met333Ile
Coding: c.999G>A
MANE Select: NM_198391
dbSNP: rs2514830526
Type: single nucleotide variant
Location: chr20:14326508 (GRCh38)

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

Disease context

hypogonadotropic hypogonadism 21 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-met333ile (accessed [today's date]).

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