Is NF1 p.Val174Phe (c.520G>T) pathogenic?

NF1 p.Val174Phe (c.520G>T) is classified Uncertain significance in NF1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-15). AlphaMissense: ambiguous (0.3903); Very rare (popmax 0.000174%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with NF1 p.Val174Phe (c.520G>T)?

NF1 p.Val174Phe (c.520G>T) is associated with Cardiovascular phenotype, neurofibromatosis, familial spinal, Watson syndrome (ClinVar).

How common is NF1 p.Val174Phe (c.520G>T) in the general population?

NF1 p.Val174Phe (c.520G>T) is very rare (popmax 0.000174%, nfe) (gnomAD).

What do computational predictors say about NF1 p.Val174Phe (c.520G>T)?

AlphaMissense predicts ambiguous (score 0.3903) — an in-silico prediction, not a clinical call.

NF1 p.Val174Phe

c.520G>T · rs1555607084 · VCV481930

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3903	ambiguous
REVEL	0.549	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 87 kb · p 4.8e-08 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000174% European (non-Finnish) · 2/1,147,824 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000142% 2/1,410,656 alleles · very rare

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: NF1
Protein: p.Val174Phe
Coding: c.520G>T
MANE Select: NM_001042492
dbSNP: rs1555607084
Type: single nucleotide variant
Location: chr17:31169931 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 174: an α-helix

Full NF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurofibromatosis, familial spinal Watson syndrome neurofibromatosis-Noonan syndrome juvenile myelomonocytic leukemia hereditary neoplastic syndrome neurofibromatosis type 1

Similar variants

NF1 p.Val174Ile Uncertain significance ★★ same residue
NF1 p.Val174fs Pathogenic ★★ same residue
NF1 c.1062+1G>A Pathogenic/Likely pathogenic ★★ same condition
NF1 c.1062+1G>C Pathogenic ★★ same condition
NF1 c.1062+2T>A Pathogenic/Likely pathogenic ★★ same condition
NF1 c.1062+2T>C Pathogenic/Likely pathogenic ★★ same condition
NF1 c.1062+3A>G Pathogenic/Likely pathogenic ★★ same condition
NF1 c.1062+3A>T Likely pathogenic ★★ 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/nf1-p-val174phe (accessed [today's date]).

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