Is NRAS p.His131= (c.393C>T) pathogenic?

NRAS p.His131= (c.393C>T) is classified Likely benign in NRAS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-13). Very rare (popmax 0.00333%, amr); Associated with RASopathy.

What condition is associated with NRAS p.His131= (c.393C>T)?

NRAS p.His131= (c.393C>T) is associated with RASopathy (ClinVar).

How common is NRAS p.His131= (c.393C>T) in the general population?

NRAS p.His131= (c.393C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

NRAS p.His131=

c.393C>T · rs745954671 · VCV477664

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

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 -1.1	GERP -5.1
Overall
CADD	6.811	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,008 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000958% 14/1,461,680 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,004
South Asian	0.0022%	45,538
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.000763%	131,091

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.His131=
Coding: c.393C>T
MANE Select: NM_002524
dbSNP: rs745954671
Type: single nucleotide variant
Location: chr1:114709626 (GRCh38)
Gene constraint: LOEUF 0.55 · pLI 0.94 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.56 · 36 PDB
Residue 131: 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.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
NRAS p.Ala91Val Uncertain significance ★★★ ⚠ same condition
NRAS p.Arg123Lys 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-his131 (accessed [today's date]).

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