Is NRAS p.Arg164Leu (c.491G>T) pathogenic?

NRAS p.Arg164Leu (c.491G>T) is classified Uncertain significance in NRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-04). AlphaMissense: likely pathogenic (0.9371); Very rare (popmax 0.000255%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with NRAS p.Arg164Leu (c.491G>T)?

NRAS p.Arg164Leu (c.491G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is NRAS p.Arg164Leu (c.491G>T) in the general population?

NRAS p.Arg164Leu (c.491G>T) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about NRAS p.Arg164Leu (c.491G>T)?

AlphaMissense predicts likely pathogenic (score 0.9371) — an in-silico prediction, not a clinical call.

NRAS p.Arg164Leu

c.491G>T · VCV3300991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9371 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9371	likely pathogenic
REVEL	0.401	indeterminate
SaProt	LLR -15.14	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 6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 7,622 bp · p 6.3e-09 · regional, not allelic
Overall
CADD	28.5	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000255% European (non-Finnish) · 3/1,178,462 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,612,162 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	63,976
European (non-Finnish)grpmax	0.000255%	392,821

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg164Leu
Coding: c.491G>T
MANE Select: NM_002524
Type: single nucleotide variant
Location: chr1:114708614 (GRCh38)
Gene constraint: LOEUF 0.55 · pLI 0.94 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.56 · 36 PDB
Residue 164: an α-helix

Full NRAS 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

Similar variants

NRAS p.Arg164Ser Uncertain significance ★★ ⚠ same residue
NRAS p.Arg164Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
NRAS p.Arg164His Uncertain significance ★ ⚠ same residue
NRAS p.Cys181Phe Uncertain significance ★★ ⚠ same condition
NRAS p.Gln129Glu Uncertain significance ★★ ⚠ same condition
NRAS p.Gly138Arg Uncertain significance ★★ ⚠ same condition
NRAS p.Ile36Thr Uncertain significance ★★ ⚠ same condition
NRAS p.Leu52Met 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-arg164leu (accessed [today's date]).

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