Is FLRT1 p.Leu336= (c.1008C>T) pathogenic?

FLRT1 p.Leu336= (c.1008C>T) is classified Benign in FLRT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-08). Common (popmax 7.39%, mid) — too common for a highly-penetrant pathogenic allele; Associated with peripheral neuropathy.

What condition is associated with FLRT1 p.Leu336= (c.1008C>T)?

FLRT1 p.Leu336= (c.1008C>T) is associated with peripheral neuropathy (ClinVar).

FLRT1 p.Leu336=

Q: How common is FLRT1 p.Leu336= (c.1008C>T) in the general population?

FLRT1 p.Leu336= (c.1008C>T) is common (popmax 7.39%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1008C>T · rs35247680 · VCV461791

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 7.39%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

peripheral neuropathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -3.7, phastCons 0.61
Overall
CADD	7.205	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.39% Middle Eastern · 448/6,060 alleles

Filtering AF 6.83% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.6%

Overall 3.77% 60,826/1,614,158 alleles · common exomes 56,914/1,461,816 · genomes 3,912/152,342 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	7.39%	14
European (non-Finnish)	4.49%	22
Ashkenazi Jewishnot grpmax-eligible	4.03%	25
Remaining individualsnot grpmax-eligible	3.72%	27
Finnishnot grpmax-eligible	2.15%	46
Admixed American	1.55%	64
South Asian	1.01%	99
African / African-American	0.908%	110
Amishnot grpmax-eligible	0.659%	152
East Asian	0.00223%	44,880

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.Leu336=
Coding: c.1008C>T
MANE Select: NM_013280
dbSNP: rs35247680
Type: single nucleotide variant
Location: chr11:64117275 (GRCh38)
Gene constraint: LOEUF 0.682 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 73.46
Residue 336: the lrrct domain

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-leu336 (accessed [today's date]).

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