Is LFNG p.Pro218Arg (c.653C>G) pathogenic?

LFNG p.Pro218Arg (c.653C>G) is classified Uncertain significance in LFNG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1479); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with LFNG p.Pro218Arg (c.653C>G)?

LFNG p.Pro218Arg (c.653C>G) is associated with Inborn genetic diseases (ClinVar).

How common is LFNG p.Pro218Arg (c.653C>G) in the general population?

LFNG p.Pro218Arg (c.653C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about LFNG p.Pro218Arg (c.653C>G)?

AlphaMissense predicts likely benign (score 0.1479) — an in-silico prediction, not a clinical call.

LFNG p.Pro218Arg

c.653C>G · VCV4097380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1479 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1479	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -6.67	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.6, phastCons 0.69
Regional constraint	o/e 1.01	unconstrained · MANE · 5,828 bp · p 0.78 · regional, not allelic
Overall
CADD	19.94	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Overall 6.2e-05% 1/1,612,464 alleles · very rare exomes 0/1,460,088 · genomes 1/152,376 · joint denominator

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.Pro218Arg
Coding: c.653C>G
MANE Select: NM_001040167
Type: single nucleotide variant
Location: chr7:2525485 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LFNG p.Pro218= Likely benign ★ same residue
LFNG p.Pro218Leu Likely benign ★ same residue
LFNG p.Ala99Thr Uncertain significance ★★ ⚠ same condition
LFNG p.Arg187Cys Uncertain significance ★★ ⚠ same condition
LFNG p.Arg341Gln Uncertain significance ★★ ⚠ same condition
LFNG p.Arg4Cys Uncertain significance ★★ ⚠ same condition
LFNG p.Asp231Asn Uncertain significance ★★ ⚠ same condition
LFNG p.Glu190Val 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-pro218arg (accessed [today's date]).

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