Is HRAS p.Arg123= (c.369C>T) pathogenic?

HRAS p.Arg123= (c.369C>T) is classified Benign in HRAS (ClinVar, Expert panel, 10 submitters; last evaluated 2017-04-18). Rare (popmax 0.241%, eas); Associated with RASopathy.

What condition is associated with HRAS p.Arg123= (c.369C>T)?

HRAS p.Arg123= (c.369C>T) is associated with RASopathy, Costello syndrome, hereditary neoplastic syndrome (ClinVar).

How common is HRAS p.Arg123= (c.369C>T) in the general population?

HRAS p.Arg123= (c.369C>T) is rare (popmax 0.241%, eas) (gnomAD).

HRAS p.Arg123=

c.369C>T · rs200945755 · VCV259747

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

rare (popmax 0.241%, eas)

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.369C>T (p.Arg123=) variant in the HRAS gene is 0.089% (13/8638) of East Asian 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.037	GERP -3.7, phastCons 0.28
Overall
CADD	9.335	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.241% East Asian · 108/44,890 alleles

Filtering AF 0.204% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.19%

Overall 0.007% 113/1,613,848 alleles · rare exomes 99/1,461,518 · genomes 14/152,330 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.241%	416
Remaining individualsnot grpmax-eligible	0.0032%	31,251
South Asian	0.0022%	45,543
European (non-Finnish)	8.47e-05%	1,179,986

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.Arg123=
Coding: c.369C>T
MANE Select: NM_005343
dbSNP: rs200945755
Type: single nucleotide variant
Location: chr11:533534 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB

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.Arg123Cys Uncertain significance ★★ ⚠ same residue
HRAS p.Arg123Pro Uncertain significance ★★ ⚠ same residue
HRAS p.Arg123Gly Uncertain significance ★ ⚠ same residue
HRAS p.Arg123His 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

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-arg123 (accessed [today's date]).

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