Is NGF p.Ala35Val (c.104C>T) pathogenic?

NGF p.Ala35Val (c.104C>T) is classified Benign in NGF (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0738); Common (popmax 45.7%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with hereditary sensory and autonomic neuropathy type 5.

What condition is associated with NGF p.Ala35Val (c.104C>T)?

NGF p.Ala35Val (c.104C>T) is associated with hereditary sensory and autonomic neuropathy type 5 (ClinVar).

What do computational predictors say about NGF p.Ala35Val (c.104C>T)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

NGF p.Ala35Val

Q: How common is NGF p.Ala35Val (c.104C>T) in the general population?

NGF p.Ala35Val (c.104C>T) is common (popmax 45.7%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.104C>T · rs6330 · VCV291993

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 45.7%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary sensory and autonomic neuropathy type 5

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -6.29	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 5.2	GERP 1.6, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 299 bp · p 0.43 · regional, not allelic
Overall
CADD	21.8	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 45.7% European (non-Finnish) · 539,143/1,179,920 alleles

Filtering AF 45.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 45.5%

Overall 41.6% 672,108/1,613,944 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	47.7%	2
Finnishnot grpmax-eligible	47.5%	2
European (non-Finnish)grpmax	45.7%	2
Ashkenazi Jewishnot grpmax-eligible	39.5%	3
Remaining individualsnot grpmax-eligible	39.4%	3
Admixed American	34.9%	3
Middle Eastern	31.9%	3
South Asian	23.3%	4
African / African-American	18.6%	5
East Asian	17.3%	6

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala35Val
Coding: c.104C>T
MANE Select: NM_002506
dbSNP: rs6330
Type: single nucleotide variant
Location: chr1:115286692 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI 0.77 (gnomAD)
Structure: AlphaFold pLDDT 73.55 · 10 PDB
Residue 35: a UniProt-annotated variant site (in)

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-ala35val (accessed [today's date]).

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