Is NRAS p.Arg164His (c.491G>A) pathogenic?

NRAS p.Arg164His (c.491G>A) is classified Uncertain significance in NRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: likely pathogenic (0.7094); Very rare (popmax 0.00892%, eas); Associated with RASopathy.

What condition is associated with NRAS p.Arg164His (c.491G>A)?

NRAS p.Arg164His (c.491G>A) is associated with RASopathy (ClinVar).

How common is NRAS p.Arg164His (c.491G>A) in the general population?

NRAS p.Arg164His (c.491G>A) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about NRAS p.Arg164His (c.491G>A)?

AlphaMissense predicts likely pathogenic (score 0.7094) — an in-silico prediction, not a clinical call.

NRAS p.Arg164His

c.491G>A · VCV4759571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7094 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.7094	likely pathogenic
REVEL	0.361	indeterminate
SaProt	LLR -13.88	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	26.2	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 0.00892% East Asian · 4/44,858 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.0013% 19/1,460,178 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,214
Finnishnot grpmax-eligible	0.00156%	63,976
European (non-Finnish)	0.0011%	90,650
South Asian	0.0011%	91,050

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.Arg164His
Coding: c.491G>A
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

RASopathy — 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.Arg164Leu 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

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-arg164his (accessed [today's date]).

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