Is LFNG p.Pro34Thr (c.100C>A) pathogenic?

LFNG p.Pro34Thr (c.100C>A) is classified Uncertain significance in LFNG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-10). AlphaMissense: likely benign (0.1071); Ultra-rare (popmax 0.0863%, afr); Associated with Inborn genetic diseases.

What condition is associated with LFNG p.Pro34Thr (c.100C>A)?

LFNG p.Pro34Thr (c.100C>A) is associated with Inborn genetic diseases, spondylocostal dysostosis 3, autosomal recessive (ClinVar).

How common is LFNG p.Pro34Thr (c.100C>A) in the general population?

LFNG p.Pro34Thr (c.100C>A) is ultra-rare (popmax 0.0863%, afr) (gnomAD).

What do computational predictors say about LFNG p.Pro34Thr (c.100C>A)?

AlphaMissense predicts likely benign (score 0.1071) — an in-silico prediction, not a clinical call.

LFNG p.Pro34Thr

c.100C>A · rs965725102 · VCV1040157

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1071 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0863%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1071	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -9.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.8, phastCons 0.97
Regional constraint	o/e 1.01	unconstrained · MANE · 5,828 bp · p 0.78 · regional, not allelic
Overall
CADD	16.96	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 0.0863% African / African-American · 49/56,780 alleles

Filtering AF 0.067% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0602%

Overall 0.00504% 50/991,580 alleles · ultra-rare exomes 7/845,722 · genomes 43/145,858 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0863%	1,159
European (non-Finnish)	0.00012%	835,890

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.Pro34Thr
Coding: c.100C>A
MANE Select: NM_001040167
dbSNP: rs965725102
Type: single nucleotide variant
Location: chr7:2519961 (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

Also linked: spondylocostal dysostosis 3, autosomal recessive

Similar variants

LFNG p.Pro34= Likely benign ★ 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
LFNG p.Arg246His 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-pro34thr (accessed [today's date]).

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