Is FLRT1 p.Arg246Cys (c.736C>T) pathogenic?

FLRT1 p.Arg246Cys (c.736C>T) is classified Uncertain significance in FLRT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-19). Very rare (popmax 0.00501%, amr); Associated with peripheral neuropathy.

What condition is associated with FLRT1 p.Arg246Cys (c.736C>T)?

FLRT1 p.Arg246Cys (c.736C>T) is associated with peripheral neuropathy (ClinVar).

How common is FLRT1 p.Arg246Cys (c.736C>T) in the general population?

FLRT1 p.Arg246Cys (c.736C>T) is very rare (popmax 0.00501%, amr) (gnomAD).

FLRT1 p.Arg246Cys

c.736C>T · rs756527574 · VCV647420

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Conditions

peripheral neuropathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.333	indeterminate
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP -0.81, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 2,021 bp · p 5.7e-12 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00501% Admixed American · 3/59,932 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00372% 60/1,612,572 alleles · very rare exomes 54/1,460,368 · genomes 6/152,204 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,977
European (non-Finnish)	0.00441%	22,689
African / African-American	0.004%	24,971
South Asian	0.0022%	45,497

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: FLRT1
Protein: p.Arg246Cys
Coding: c.736C>T
MANE Select: NM_013280
dbSNP: rs756527574
Type: single nucleotide variant
Location: chr11:64117003 (GRCh38)
Gene constraint: LOEUF 0.682 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 73.46

Full FLRT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peripheral neuropathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FLRT1 p.Ala148Gly Uncertain significance ★★ same condition
FLRT1 p.Ala461Thr Uncertain significance ★★ same condition
FLRT1 p.Arg149Cys Uncertain significance ★★ same condition
FLRT1 p.Arg326Lys Uncertain significance ★★ same condition
FLRT1 p.Arg452His Uncertain significance ★★ same condition
FLRT1 p.Arg586Gln Uncertain significance ★★ same condition
FLRT1 p.Arg592Gln Uncertain significance ★★ same condition
FLRT1 p.Arg592Trp Uncertain significance ★★ same condition

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/flrt1-p-arg246cys (accessed [today's date]).

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