Is NRAS p.Arg68Ser (c.204A>T) pathogenic?

NRAS p.Arg68Ser (c.204A>T) is classified Likely pathogenic in NRAS (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9989); Absent from gnomAD v4.1; Associated with Noonan syndrome.

What condition is associated with NRAS p.Arg68Ser (c.204A>T)?

NRAS p.Arg68Ser (c.204A>T) is associated with Noonan syndrome (ClinVar).

How common is NRAS p.Arg68Ser (c.204A>T) in the general population?

NRAS p.Arg68Ser (c.204A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NRAS p.Arg68Ser (c.204A>T)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

NRAS p.Arg68Ser

c.204A>T · rs2526451293 · VCV981556

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Noonan syndrome

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic ✓ concordant with ClinVar
REVEL	0.624	indeterminate
SaProt	LLR -14.41	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -2.1, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 7,622 bp · p 6.3e-09 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NRAS
Protein: p.Arg68Ser
Coding: c.204A>T
MANE Select: NM_002524
dbSNP: rs2526451293
Type: single nucleotide variant
Location: chr1:114713886 (GRCh38)
Gene constraint: LOEUF 0.55 · pLI 0.94 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.56 · 36 PDB
Residue 68: an α-helix

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

Disease context

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

Similar variants

NRAS p.Arg68Thr Uncertain significance ★★ ⚠ same residue
NRAS p.Arg68Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
NRAS p.Gly12Ser Pathogenic ★★★ same condition
NRAS p.Thr50Ile Pathogenic ★★★ same condition
NRAS p.Thr58Ile Pathogenic ★★★ same condition
NRAS p.Pro185Ser Uncertain significance ★★★ ⚠ same condition
NRAS p.Gly12Val Pathogenic/Likely pathogenic ★★ same condition
NRAS p.Glu153Lys 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-arg68ser (accessed [today's date]).

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