Is LFNG p.Arg263His (c.788G>A) pathogenic?

LFNG p.Arg263His (c.788G>A) is classified Uncertain significance in LFNG (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-19). AlphaMissense: likely benign (0.1611); Ultra-rare (popmax 0.0851%, nfe); Associated with spondylocostal dysostosis 3, autosomal recessive.

What condition is associated with LFNG p.Arg263His (c.788G>A)?

LFNG p.Arg263His (c.788G>A) is associated with spondylocostal dysostosis 3, autosomal recessive (ClinVar).

How common is LFNG p.Arg263His (c.788G>A) in the general population?

LFNG p.Arg263His (c.788G>A) is ultra-rare (popmax 0.0851%, nfe) (gnomAD).

What do computational predictors say about LFNG p.Arg263His (c.788G>A)?

AlphaMissense predicts likely benign (score 0.1611) — an in-silico prediction, not a clinical call.

LFNG p.Arg263His

c.788G>A · rs201864741 · VCV1063078

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1611 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0851%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spondylocostal dysostosis 3, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.1611	likely benign
REVEL	0.744	pathogenic-leaning
SaProt	LLR -10.95	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.32	constrained · MANE · 64 bp · p 0.00015 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0851% European (non-Finnish) · 1,004/1,180,012 alleles

Filtering AF 0.0807% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.079%

Overall 0.0646% 1,041/1,612,638 alleles · ultra-rare exomes 1,009/1,460,232 · genomes 32/152,406 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0851%	1,175
Remaining individualsnot grpmax-eligible	0.04%	2,499
Admixed American	0.0117%	8,576
African / African-American	0.004%	25,025
Finnishnot grpmax-eligible	0.0016%	62,640
South Asian	0.0011%	91,078

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.Arg263His
Coding: c.788G>A
MANE Select: NM_001040167
dbSNP: rs201864741
Type: single nucleotide variant
Location: chr7:2525737 (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.Arg263Leu Uncertain significance ★ ⚠ same residue
LFNG p.Arg263Cys Uncertain significance ★ ⚠ same residue
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

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-arg263his (accessed [today's date]).

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