Is HRAS p.Leu159= (c.477G>A) pathogenic?

HRAS p.Leu159= (c.477G>A) is classified Benign in HRAS (ClinVar, Expert panel, 17 submitters; last evaluated 2017-04-18). Rare (popmax 0.456%, nfe); Associated with RASopathy.

What condition is associated with HRAS p.Leu159= (c.477G>A)?

HRAS p.Leu159= (c.477G>A) is associated with RASopathy, Costello syndrome, hereditary neoplastic syndrome (ClinVar).

How common is HRAS p.Leu159= (c.477G>A) in the general population?

HRAS p.Leu159= (c.477G>A) is rare (popmax 0.456%, nfe) (gnomAD).

HRAS p.Leu159=

c.477G>A · rs140060409 · VCV40446

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 17 submitters

gnomAD v4.1

Rare

rare (popmax 0.456%, nfe)

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.477G>A (p.Leu159=) variant in the HRAS gene is 0.185% (140/65296) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

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 0.07	GERP -3.7, phastCons 0.92
Overall
CADD	6.988	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.456% European (non-Finnish) · 5,377/1,179,994 alleles

Filtering AF 0.445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.441%

Overall 0.356% 5,744/1,613,094 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.456%	219
Remaining individualsnot grpmax-eligible	0.274%	365
Admixed American	0.202%	496
African / African-American	0.0839%	1,191
Middle Eastern	0.033%	3,031
Finnishnot grpmax-eligible	0.0159%	6,297

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: HRAS
Protein: p.Leu159=
Coding: c.477G>A
MANE Select: NM_005343
dbSNP: rs140060409
Type: single nucleotide variant
Location: chr11:532729 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 159: an α-helix

Full HRAS 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

Also linked: Costello syndrome hereditary neoplastic syndrome Noonan syndrome and Noonan-related syndrome

Similar variants

HRAS p.Leu159Phe Uncertain significance ★ ⚠ same residue
HRAS p.Leu159Ser Uncertain significance ★ ⚠ same residue
HRAS p.Ser159Asn Uncertain significance ★ same residue
HRAS p.Ala59Thr Likely pathogenic ★★★ same condition
HRAS p.Gly12Ser Pathogenic ★★★ same condition
HRAS p.Gly13Cys Pathogenic ★★★ same condition
HRAS p.Lys117Arg Pathogenic ★★★ same condition
HRAS 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/hras-p-leu159 (accessed [today's date]).

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