Is NGF p.Ala18Val (c.53C>T) pathogenic?

NGF p.Ala18Val (c.53C>T) is classified Uncertain significance in NGF (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-08). AlphaMissense: ambiguous (0.3967); Ultra-rare (popmax 0.0164%, mid); Associated with hereditary sensory and autonomic neuropathy type 5.

What condition is associated with NGF p.Ala18Val (c.53C>T)?

NGF p.Ala18Val (c.53C>T) is associated with hereditary sensory and autonomic neuropathy type 5 (ClinVar).

How common is NGF p.Ala18Val (c.53C>T) in the general population?

NGF p.Ala18Val (c.53C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about NGF p.Ala18Val (c.53C>T)?

AlphaMissense predicts ambiguous (score 0.3967) — an in-silico prediction, not a clinical call.

NGF p.Ala18Val

Q: How is Hereditary sensory and autonomic neuropathy type 5 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.53C>T · rs754287903 · VCV526746

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3967 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary sensory and autonomic neuropathy type 5

Computational evidence

Protein change
AlphaMissense	0.3967	ambiguous
REVEL	0.664	pathogenic-leaning
SaProt	LLR -8.88	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.28	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 9.9	GERP 2.5, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 299 bp · p 0.43 · regional, not allelic
Overall
CADD	31.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00415% 67/1,614,020 alleles · ultra-rare exomes 64/1,461,882 · genomes 3/152,138 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0112%	8,927
European (non-Finnish)	0.00466%	21,455
African / African-American	0.00267%	37,457
East Asian	0.00223%	44,882
South Asian	0.0011%	91,076

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.Ala18Val
Coding: c.53C>T
MANE Select: NM_002506
dbSNP: rs754287903
Type: single nucleotide variant
Location: chr1:115286743 (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

hereditary sensory and autonomic neuropathy type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary sensory and autonomic neuropathy type 5 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

NGF p.Ala18= Benign ★★ same residue
NGF p.Arg221Trp Likely pathogenic ★★ same condition
NGF p.Ala11Thr 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
NGF p.Arg49Cys 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-ala18val (accessed [today's date]).

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