Is LFNG p.Leu2= (c.6C>A) pathogenic?

LFNG p.Leu2= (c.6C>A) is classified Likely benign in LFNG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-17). Ultra-rare (popmax 0.0937%, amr); Associated with spondylocostal dysostosis 3, autosomal recessive.

What condition is associated with LFNG p.Leu2= (c.6C>A)?

LFNG p.Leu2= (c.6C>A) is associated with spondylocostal dysostosis 3, autosomal recessive (ClinVar).

How common is LFNG p.Leu2= (c.6C>A) in the general population?

LFNG p.Leu2= (c.6C>A) is ultra-rare (popmax 0.0937%, amr) (gnomAD).

LFNG p.Leu2=

c.6C>A · rs1390203183 · VCV731865

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0937%, amr)

Conditions

spondylocostal dysostosis 3, autosomal recessive

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 0.044	GERP -1.7, phastCons 0.93
Overall
CADD	10.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0937% Admixed American · 20/21,354 alleles

Filtering AF 0.062% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0518%

Overall 0.0019% 21/1,102,440 alleles · ultra-rare exomes 16/953,630 · genomes 5/148,810 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0937%	1,068
Remaining individualsnot grpmax-eligible	0.00281%	35,530

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: LFNG
Protein: p.Leu2=
Coding: c.6C>A
MANE Select: NM_001040167
dbSNP: rs1390203183
Type: single nucleotide variant
Location: chr7:2519867 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI 0.02 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.66

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

Disease context

spondylocostal dysostosis 3, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LFNG p.Thr145Met Likely pathogenic ★★ same condition
LFNG c.482-3C>T Uncertain significance ★★ same condition
LFNG p.Ala95Val Uncertain significance ★★ ⚠ same condition
LFNG p.Ala99Thr Uncertain significance ★★ ⚠ same condition
LFNG p.Arg187Cys Uncertain significance ★★ ⚠ same condition
LFNG p.Arg239Trp Uncertain significance ★★ ⚠ same condition
LFNG p.Arg246His Uncertain significance ★★ ⚠ same condition
LFNG p.Arg341Gln 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/lfng-p-leu2 (accessed [today's date]).

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