Is NGF p.Pro112Arg (c.335C>G) pathogenic?

NGF p.Pro112Arg (c.335C>G) is classified Uncertain significance in NGF (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-04-24). AlphaMissense: likely benign (0.0868); Ultra-rare (popmax 0.0121%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NGF p.Pro112Arg (c.335C>G)?

NGF p.Pro112Arg (c.335C>G) is associated with Inborn genetic diseases, hereditary sensory and autonomic neuropathy type 5 (ClinVar).

How common is NGF p.Pro112Arg (c.335C>G) in the general population?

NGF p.Pro112Arg (c.335C>G) is ultra-rare (popmax 0.0121%, nfe) (gnomAD).

What do computational predictors say about NGF p.Pro112Arg (c.335C>G)?

AlphaMissense predicts likely benign (score 0.0868) — an in-silico prediction, not a clinical call.

NGF p.Pro112Arg

c.335C>G · rs147763877 · VCV291990

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0868 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0868	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -6.57	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 7.2	GERP -0.56, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 422 bp · p 3.2e-05 · regional, not allelic
Overall
CADD	11.68	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 0.0121% European (non-Finnish) · 143/1,179,822 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00981%

Overall 0.00967% 156/1,613,744 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0121%	8,250
Remaining individualsnot grpmax-eligible	0.0112%	8,929
South Asian	0.00329%	30,353
African / African-American	0.00267%	37,487
Admixed American	0.00167%	60,014

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: NGF
Protein: p.Pro112Arg
Coding: c.335C>G
MANE Select: NM_002506
dbSNP: rs147763877
Type: single nucleotide variant
Location: chr1:115286461 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI 0.77 (gnomAD)
Structure: AlphaFold pLDDT 73.55 · 10 PDB

Full NGF 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: hereditary sensory and autonomic neuropathy type 5

Similar variants

NGF p.Pro112His Uncertain significance ★ ⚠ same residue
NGF p.Arg221Trp Likely pathogenic ★★ same condition
NGF p.Ala11Thr Uncertain significance ★★ ⚠ same condition
NGF p.Ala18Val Uncertain significance ★★ ⚠ same condition
NGF p.Ala54Thr Uncertain significance ★★ ⚠ same condition
NGF p.Arg121Trp Uncertain significance ★★ ⚠ same condition
NGF p.Arg130Gly Uncertain significance ★★ ⚠ same condition
NGF p.Arg180Gln 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/ngf-p-pro112arg (accessed [today's date]).

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