Is NF1 p.Thr2135Pro (c.6403A>C) pathogenic?

NF1 p.Thr2135Pro (c.6403A>C) is classified Uncertain significance in NF1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-29). AlphaMissense: likely pathogenic (0.9808); Very rare (popmax 8.47e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with NF1 p.Thr2135Pro (c.6403A>C)?

NF1 p.Thr2135Pro (c.6403A>C) is associated with Cardiovascular phenotype, hereditary neoplastic syndrome, neurofibromatosis type 1 (ClinVar).

How common is NF1 p.Thr2135Pro (c.6403A>C) in the general population?

NF1 p.Thr2135Pro (c.6403A>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about NF1 p.Thr2135Pro (c.6403A>C)?

AlphaMissense predicts likely pathogenic (score 0.9808) — an in-silico prediction, not a clinical call.

NF1 p.Thr2135Pro

c.6403A>C · rs1555534767 · VCV484067

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9808 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9808	likely pathogenic
REVEL	0.927	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 9,812 bp · p 2.1e-34 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,990 alleles

Overall 6.85e-05% 1/1,459,620 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.Thr2135Pro
Coding: c.6403A>C
MANE Select: NM_001042492
dbSNP: rs1555534767
Type: single nucleotide variant
Location: chr17:31336890 (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.Thr2135Ile Pathogenic/Likely pathogenic ★★ same residue
NF1 p.Thr2135Ala Uncertain significance ★★ ⚠ same residue
NF1 p.Thr2135Ser Uncertain significance ★ ⚠ same residue
NF1 p.Thr2135= Likely benign ★ 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-thr2135pro (accessed [today's date]).

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