Is NGF p.Val143Ala (c.428T>C) pathogenic?

NGF p.Val143Ala (c.428T>C) is classified Uncertain significance in NGF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-13). AlphaMissense: likely pathogenic (0.6139); Ultra-rare (popmax 0.03%, amr); Associated with hereditary sensory and autonomic neuropathy type 5.

What condition is associated with NGF p.Val143Ala (c.428T>C)?

NGF p.Val143Ala (c.428T>C) is associated with hereditary sensory and autonomic neuropathy type 5 (ClinVar).

How common is NGF p.Val143Ala (c.428T>C) in the general population?

NGF p.Val143Ala (c.428T>C) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about NGF p.Val143Ala (c.428T>C)?

AlphaMissense predicts likely pathogenic (score 0.6139) — an in-silico prediction, not a clinical call.

NGF p.Val143Ala

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.428T>C · rs758273427 · VCV2420228

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6139 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary sensory and autonomic neuropathy type 5

Computational evidence

Protein change
AlphaMissense	0.6139	likely pathogenic
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -7.45	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 422 bp · p 3.2e-05 · regional, not allelic
Overall
CADD	25.7	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 0.03% Admixed American · 18/59,954 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00136% 22/1,613,650 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,331
Remaining individualsnot grpmax-eligible	0.0032%	31,239
European (non-Finnish)	0.000169%	589,988

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.Val143Ala
Coding: c.428T>C
MANE Select: NM_002506
dbSNP: rs758273427
Type: single nucleotide variant
Location: chr1:115286368 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI 0.77 (gnomAD)
Structure: AlphaFold pLDDT 73.55 · 10 PDB
Residue 143: a β-strand; a disulfide bond

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.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
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-val143ala (accessed [today's date]).

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