Is LFNG p.Asp222= (c.666C>T) pathogenic?

LFNG p.Asp222= (c.666C>T) is classified Likely benign in LFNG (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-14). Ultra-rare (popmax 0.0156%, eas); Associated with spondylocostal dysostosis 3, autosomal recessive.

What condition is associated with LFNG p.Asp222= (c.666C>T)?

LFNG p.Asp222= (c.666C>T) is associated with spondylocostal dysostosis 3, autosomal recessive (ClinVar).

How common is LFNG p.Asp222= (c.666C>T) in the general population?

LFNG p.Asp222= (c.666C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

LFNG p.Asp222=

c.666C>T · rs767087803 · VCV2166342

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.9	GERP -3.5
Overall
CADD	8.493	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,880 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00161% 26/1,612,348 alleles · ultra-rare exomes 24/1,459,970 · genomes 2/152,378 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,411
African / African-American	0.004%	25,021
South Asian	0.0022%	45,532
Admixed American	0.00167%	59,972
Remaining individualsnot grpmax-eligible	0.0016%	62,438
European (non-Finnish)	0.00102%	98,323

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.Asp222=
Coding: c.666C>T
MANE Select: NM_001040167
dbSNP: rs767087803
Type: single nucleotide variant
Location: chr7:2525498 (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-asp222 (accessed [today's date]).

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