Is HRAS p.His27= (c.81T>C) pathogenic?

HRAS p.His27= (c.81T>C) is classified Benign in HRAS (ClinVar, Expert panel, 19 submitters; last evaluated 2017-04-03). Common (popmax 37.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with RASopathy.

What condition is associated with HRAS p.His27= (c.81T>C)?

HRAS p.His27= (c.81T>C) is associated with RASopathy, squamous cell lung carcinoma, Costello syndrome (ClinVar).

HRAS p.His27=

Q: How common is HRAS p.His27= (c.81T>C) in the general population?

HRAS p.His27= (c.81T>C) is common (popmax 37.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.81T>C · rs12628 · VCV40431

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 19 submitters

gnomAD v4.1

Common

common (popmax 37.8%, afr) — too common for a highly-penetrant pathogenic allele

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.81T>C (p.His27=) variant in the HRAS gene is 36.7% for African chromosomes by the Exome Aggregation Consortium (3874/10274 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additional case-level data provided by: SCV000058315; SCV000062146; SCV000196686.

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 2.3	GERP -0.68, phastCons 1
Overall
CADD	5.67	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 37.8% African / African-American · 28,297/74,940 alleles

Filtering AF 37.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 37.2%

Overall 33.1% 534,272/1,612,572 alleles · common exomes 482,463/1,460,504 · genomes 51,809/152,068 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	37.8%	3
Admixed American	37.6%	3
Amishnot grpmax-eligible	35.3%	3
European (non-Finnish)	34.4%	3
Remaining individualsnot grpmax-eligible	31.3%	3
Finnishnot grpmax-eligible	27.4%	4
Ashkenazi Jewishnot grpmax-eligible	27%	4
Middle Eastern	27%	4
South Asian	25.4%	4
East Asian	18%	6

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.His27=
Coding: c.81T>C
MANE Select: NM_005343
dbSNP: rs12628
Type: single nucleotide variant
Location: chr11:534242 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 27: a β-strand

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: squamous cell lung carcinoma Costello syndrome Noonan syndrome and Noonan-related syndrome

Similar variants

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
HRAS p.Gly138Ser Uncertain significance ★★★ ⚠ same condition
HRAS p.Ile93Val Uncertain significance ★★★ ⚠ same condition
HRAS p.Lys170Ter 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/hras-p-his27 (accessed [today's date]).

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