Is FLRT3 p.Thr419Ser (c.1255A>T) pathogenic?

FLRT3 p.Thr419Ser (c.1255A>T) is classified Uncertain significance in FLRT3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-21). AlphaMissense: likely benign (0.0602); Rare (popmax 0.149%, mid); Associated with hypogonadotropic hypogonadism 21 with or without anosmia.

What condition is associated with FLRT3 p.Thr419Ser (c.1255A>T)?

FLRT3 p.Thr419Ser (c.1255A>T) is associated with hypogonadotropic hypogonadism 21 with or without anosmia (ClinVar).

How common is FLRT3 p.Thr419Ser (c.1255A>T) in the general population?

FLRT3 p.Thr419Ser (c.1255A>T) is rare (popmax 0.149%, mid) (gnomAD).

What do computational predictors say about FLRT3 p.Thr419Ser (c.1255A>T)?

AlphaMissense predicts likely benign (score 0.0602) — an in-silico prediction, not a clinical call.

FLRT3 p.Thr419Ser

c.1255A>T · rs769008665 · VCV1029224

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0602 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypogonadotropic hypogonadism 21 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.0602	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -5.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,946 bp · p 4e-08 · regional, not allelic
Overall
CADD	18.62	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 0.149% Middle Eastern · 9/6,058 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0579%

Overall 0.0126% 203/1,613,890 alleles · rare exomes 188/1,461,670 · genomes 15/152,220 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.149%	673
Remaining individualsnot grpmax-eligible	0.032%	3,125
African / African-American	0.0133%	7,502
European (non-Finnish)	0.0132%	7,563
Admixed American	0.00834%	11,997
South Asian	0.00329%	30,360

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.Thr419Ser
Coding: c.1255A>T
MANE Select: NM_198391
dbSNP: rs769008665
Type: single nucleotide variant
Location: chr20:14326252 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 74.57 · 3 PDB
Residue 419: the fibronectin type-iii domain

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

Similar variants

FLRT3 p.Ala576Val Uncertain significance ★ same condition
FLRT3 p.Pro389Leu Uncertain significance ★ ⚠ same condition
FLRT3 p.Lys339Arg Pathogenic ⚠ same condition
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

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-thr419ser (accessed [today's date]).

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