Is LFNG p.Thr25= (c.75C>T) pathogenic?

LFNG p.Thr25= (c.75C>T) is classified Benign/Likely benign in LFNG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-27). Rare (popmax 0.787%, mid); Associated with spondylocostal dysostosis 3, autosomal recessive.

What condition is associated with LFNG p.Thr25= (c.75C>T)?

LFNG p.Thr25= (c.75C>T) is associated with spondylocostal dysostosis 3, autosomal recessive (ClinVar).

How common is LFNG p.Thr25= (c.75C>T) in the general population?

LFNG p.Thr25= (c.75C>T) is rare (popmax 0.787%, mid) (gnomAD).

LFNG p.Thr25=

c.75C>T · rs767338996 · VCV1165699

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.787%, mid)

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 -3.7	GERP -1.5
Overall
CADD	6.087	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.787% Middle Eastern · 17/2,160 alleles

Filtering AF 0.501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.412%

Overall 0.275% 2,820/1,025,050 alleles · rare exomes 2,502/879,396 · genomes 318/145,654 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.56%	39
Middle Easterngrpmax	0.787%	127
South Asian	0.474%	211
Ashkenazi Jewishnot grpmax-eligible	0.341%	293
European (non-Finnish)	0.291%	343
Remaining individualsnot grpmax-eligible	0.261%	383
Admixed American	0.158%	633
African / African-American	0.0437%	2,289
Finnishnot grpmax-eligible	0.0156%	6,424

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr25=
Coding: c.75C>T
MANE Select: NM_001040167
dbSNP: rs767338996
Type: single nucleotide variant
Location: chr7:2519936 (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-thr25 (accessed [today's date]).

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