Is NF1 p.Ser2191Pro (c.6571T>C) pathogenic?

NF1 p.Ser2191Pro (c.6571T>C) is classified Conflicting classifications of pathogenicity in NF1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-04). AlphaMissense: likely benign (0.1736); Very rare (popmax 0.00133%, afr); Associated with Cardiovascular phenotype.

What condition is associated with NF1 p.Ser2191Pro (c.6571T>C)?

NF1 p.Ser2191Pro (c.6571T>C) is associated with Cardiovascular phenotype, hereditary neoplastic syndrome, neurofibromatosis type 1 (ClinVar).

How common is NF1 p.Ser2191Pro (c.6571T>C) in the general population?

NF1 p.Ser2191Pro (c.6571T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about NF1 p.Ser2191Pro (c.6571T>C)?

AlphaMissense predicts likely benign (score 0.1736) — an in-silico prediction, not a clinical call.

NF1 p.Ser2191Pro

c.6571T>C · rs754630324 · VCV852744

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1736 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1736	likely benign
REVEL	0.35	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 9,812 bp · p 2.1e-34 · regional, not allelic
Overall
CADD	24.0	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 0.00133% African / African-American · 1/75,046 alleles

Overall 6.2e-05% 1/1,614,098 alleles · very rare exomes 1/1,461,822 · genomes 0/152,276 · joint denominator

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.Ser2191Pro
Coding: c.6571T>C
MANE Select: NM_001042492
dbSNP: rs754630324
Type: single nucleotide variant
Location: chr17:31337511 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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: hereditary neoplastic syndrome neurofibromatosis type 1

Similar variants

NF1 p.Ser2191= Likely benign ★★ same residue
NF1 p.Ser2191Ala Uncertain significance ★ ⚠ same residue
NF1 p.Ser2191Cys Uncertain significance ★ ⚠ same residue
NF1 p.Ser2191Phe Conflicting classifications of pathogenicity ★ ⚠ 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

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-ser2191pro (accessed [today's date]).

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