Is NF1 p.Pro678= (c.2034G>A) pathogenic?

NF1 p.Pro678= (c.2034G>A) is classified Benign in NF1 (ClinVar, Multiple submitters, 19 submitters; last evaluated 2026-05-15). Common (popmax 67.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with NF1 p.Pro678= (c.2034G>A)?

NF1 p.Pro678= (c.2034G>A) is associated with hereditary neoplastic syndrome, neurofibromatosis, familial spinal, Watson syndrome (ClinVar).

NF1 p.Pro678=

Q: How common is NF1 p.Pro678= (c.2034G>A) in the general population?

NF1 p.Pro678= (c.2034G>A) is common (popmax 67.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2034G>A · rs2285892 · VCV183826

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 19 submitters

gnomAD v4.1

Common

common (popmax 67.9%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -3.2
Overall
CADD	3.58	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 67.9% African / African-American · 50,834/74,838 alleles

Filtering AF 67.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 67.2%

Overall 33.6% 542,388/1,613,246 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	67.9%	1
East Asian	53.8%	2
Admixed American	47.2%	2
South Asian	36.8%	3
Finnishnot grpmax-eligible	34.3%	3
Remaining individualsnot grpmax-eligible	33.5%	3
European (non-Finnish)	30%	3
Amishnot grpmax-eligible	28%	4
Ashkenazi Jewishnot grpmax-eligible	22.9%	4
Middle Eastern	22.5%	4

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.Pro678=
Coding: c.2034G>A
MANE Select: NM_001042492
dbSNP: rs2285892
Type: single nucleotide variant
Location: chr17:31226467 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 678: an α-helix; a UniProt-annotated variant site (in)

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurofibromatosis, familial spinal Watson syndrome neurofibromatosis-Noonan syndrome neurofibromatosis type 1

Similar variants

NF1 p.Pro678Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
NF1 p.Pro678Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
NF1 p.Pro678Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
NF1 p.Pro678Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
NF1 p.Pro678fs Pathogenic ★★ same residue
NF1 p.Pro678Ile Uncertain significance ★ same residue
NF1 c.1062+1G>A Pathogenic/Likely pathogenic ★★ same condition
NF1 c.1062+1G>C 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-pro678 (accessed [today's date]).

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