Is FLRT1 p.Ile653Thr (c.1958T>C) pathogenic?

FLRT1 p.Ile653Thr (c.1958T>C) is classified Conflicting classifications of pathogenicity in FLRT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-23). Rare (popmax 0.225%, eas); Associated with peripheral neuropathy.

What condition is associated with FLRT1 p.Ile653Thr (c.1958T>C)?

FLRT1 p.Ile653Thr (c.1958T>C) is associated with peripheral neuropathy (ClinVar).

How common is FLRT1 p.Ile653Thr (c.1958T>C) in the general population?

FLRT1 p.Ile653Thr (c.1958T>C) is rare (popmax 0.225%, eas) (gnomAD).

FLRT1 p.Ile653Thr

c.1958T>C · rs79628679 · VCV461800

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.225%, eas)

Conditions

peripheral neuropathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.053	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -0.23, phastCons 0.27
Regional constraint	o/e 0.78	unconstrained · MANE · 2,021 bp · p 5.7e-12 · regional, not allelic
Overall
CADD	16.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.225% East Asian · 101/44,872 alleles

Filtering AF 0.19% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.176%

Overall 0.0207% 334/1,612,654 alleles · rare exomes 302/1,460,316 · genomes 32/152,338 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.225%	444
Remaining individualsnot grpmax-eligible	0.0176%	5,679
Middle Eastern	0.0165%	6,058
European (non-Finnish)	0.0163%	6,143
Admixed American	0.015%	6,665
South Asian	0.0132%	7,586
African / African-American	0.00933%	10,723
Finnishnot grpmax-eligible	0.00158%	63,330

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.Ile653Thr
Coding: c.1958T>C
MANE Select: NM_013280
dbSNP: rs79628679
Type: single nucleotide variant
Location: chr11:64118225 (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-ile653thr (accessed [today's date]).

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