Is NRAS p.Glu49Asp (c.147A>C) pathogenic?

NRAS p.Glu49Asp (c.147A>C) is classified Uncertain significance in NRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2017-11-29). AlphaMissense: ambiguous (0.4601); Very rare (popmax 0.00134%, afr).

How common is NRAS p.Glu49Asp (c.147A>C) in the general population?

NRAS p.Glu49Asp (c.147A>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about NRAS p.Glu49Asp (c.147A>C)?

AlphaMissense predicts ambiguous (score 0.4601) — an in-silico prediction, not a clinical call.

NRAS p.Glu49Asp

c.147A>C · rs1370520807 · VCV561699

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4601 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4601	ambiguous
REVEL	0.286	benign-leaning
SaProt	LLR -11.60	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.47	GERP -0.93, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 7,622 bp · p 6.3e-09 · regional, not allelic
Overall
CADD	21.3	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

Grpmax group 0.00134% African / African-American · 1/74,674 alleles

Overall 0.000658% 1/151,962 alleles · very rare

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.Glu49Asp
Coding: c.147A>C
MANE Select: NM_002524
dbSNP: rs1370520807
Type: single nucleotide variant
Location: chr1:114713943 (GRCh38)
Gene constraint: LOEUF 0.55 · pLI 0.94 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.56 · 36 PDB
Residue 49: a β-strand

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

Similar variants

NRAS p.Glu49Gln Uncertain significance ★ ⚠ same residue
NRAS p.Gly12Ser Pathogenic ★★★ same type
NRAS p.Gly60Glu Pathogenic ★★★ same type
NRAS p.Ile24Asn Likely pathogenic ★★★ same type
NRAS p.Thr50Ile Pathogenic ★★★ ⚠ same type
NRAS p.Thr58Ile Pathogenic ★★★ same type
NRAS p.Ala11Thr Uncertain significance ★★★ ⚠ same type
NRAS p.Ala91Val Uncertain significance ★★★ ⚠ same type

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-glu49asp (accessed [today's date]).

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