Is FLRT3 p.Thr419= (c.1257C>T) pathogenic?

FLRT3 p.Thr419= (c.1257C>T) is classified Benign in FLRT3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 43.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hypogonadotropic hypogonadism 21 with or without anosmia.

What condition is associated with FLRT3 p.Thr419= (c.1257C>T)?

FLRT3 p.Thr419= (c.1257C>T) is associated with hypogonadotropic hypogonadism 21 with or without anosmia (ClinVar).

FLRT3 p.Thr419=

Q: How common is FLRT3 p.Thr419= (c.1257C>T) in the general population?

FLRT3 p.Thr419= (c.1257C>T) is common (popmax 43.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1257C>T · rs6042672 · VCV1226971

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 43.3%, afr) — too common for a highly-penetrant pathogenic allele

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
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.6	GERP 1.3, phastCons 1
Overall
CADD	6.224	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 43.3% African / African-American · 32,445/74,926 alleles

Filtering AF 42.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 42.7%

Overall 27.3% 440,477/1,613,644 alleles · common exomes 392,958/1,461,606 · genomes 47,519/152,038 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	43.3%	2
Amishnot grpmax-eligible	36.9%	3
Middle Eastern	34.1%	3
East Asian	32.2%	3
South Asian	32%	3
Remaining individualsnot grpmax-eligible	28.8%	3
Finnishnot grpmax-eligible	27.4%	4
European (non-Finnish)	26.1%	4
Ashkenazi Jewishnot grpmax-eligible	25.6%	4
Admixed American	17.3%	6

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.Thr419=
Coding: c.1257C>T
MANE Select: NM_198391
dbSNP: rs6042672
Type: single nucleotide variant
Location: chr20:14326250 (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-thr419 (accessed [today's date]).

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