Is NF1 p.Phe71Ser (c.212T>C) pathogenic?

NF1 p.Phe71Ser (c.212T>C) is classified Conflicting classifications of pathogenicity in NF1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-25). AlphaMissense: likely pathogenic (0.7607); Very rare (popmax 0.000435%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with NF1 p.Phe71Ser (c.212T>C)?

NF1 p.Phe71Ser (c.212T>C) is associated with hereditary neoplastic syndrome, neurofibromatosis, familial spinal, Watson syndrome (ClinVar).

How common is NF1 p.Phe71Ser (c.212T>C) in the general population?

NF1 p.Phe71Ser (c.212T>C) is very rare (popmax 0.000435%, nfe) (gnomAD).

What do computational predictors say about NF1 p.Phe71Ser (c.212T>C)?

AlphaMissense predicts likely pathogenic (score 0.7607) — an in-silico prediction, not a clinical call.

NF1 p.Phe71Ser

c.212T>C · rs752396270 · VCV187703

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7607 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000435%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7607	likely pathogenic
REVEL	0.246	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 87 kb · p 4.8e-08 · regional, not allelic
Overall
CADD	24.9	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 0.000435% European (non-Finnish) · 5/1,148,890 alleles

Filtering AF 0.000128% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.3e-05%

Overall 0.000317% 5/1,579,592 alleles · very rare exomes 3/1,427,414 · genomes 2/152,178 · 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.Phe71Ser
Coding: c.212T>C
MANE Select: NM_001042492
dbSNP: rs752396270
Type: single nucleotide variant
Location: chr17:31159017 (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

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

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

Similar variants

NF1 p.Phe71fs 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
NF1 c.1063-13G>A 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-phe71ser (accessed [today's date]).

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