Is NRAS p.Phe28= (c.84T>C) pathogenic?

NRAS p.Phe28= (c.84T>C) is classified Likely benign in NRAS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-30). Very rare (popmax 0.00229%, nfe); Associated with RASopathy.

What condition is associated with NRAS p.Phe28= (c.84T>C)?

NRAS p.Phe28= (c.84T>C) is associated with RASopathy (ClinVar).

How common is NRAS p.Phe28= (c.84T>C) in the general population?

NRAS p.Phe28= (c.84T>C) is very rare (popmax 0.00229%, nfe) (gnomAD).

NRAS p.Phe28=

c.84T>C · rs1328445116 · VCV2041687

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Conditions

RASopathy

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 3.6	GERP 0.12, phastCons 1
Overall
CADD	13.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00229% European (non-Finnish) · 27/1,179,478 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00192% 28/1,461,246 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,684
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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: NRAS
Protein: p.Phe28=
Coding: c.84T>C
MANE Select: NM_002524
dbSNP: rs1328445116
Type: single nucleotide variant
Location: chr1:114716077 (GRCh38)
Gene constraint: LOEUF 0.55 · pLI 0.94 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.56 · 36 PDB

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

Disease context

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

Similar variants

NRAS p.Phe28Tyr Uncertain significance ★ ⚠ same residue
NRAS p.Phe28Cys Uncertain significance ★ ⚠ same residue
NRAS p.Gly12Ser Pathogenic ★★★ same condition
NRAS p.Gly60Glu Pathogenic ★★★ same condition
NRAS p.Ile24Asn Likely pathogenic ★★★ same condition
NRAS p.Thr50Ile Pathogenic ★★★ ⚠ same condition
NRAS p.Thr58Ile Pathogenic ★★★ same condition
NRAS p.Ala11Thr Uncertain significance ★★★ ⚠ 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/nras-p-phe28 (accessed [today's date]).

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