# NM_005343.4(HRAS):c.228G>A (p.Glu76=)

https://sugi.bio/variant/hras-p-glu76

## Summary

**HRAS p.Glu76= (c.228G>A)** is classified **Likely benign** in HRAS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-29). Very rare (popmax 0.00133%, afr); Associated with Costello syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1057522598 · 2 submitters · 1 linked condition · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the HRAS gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Costello syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 8 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001550/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HRAS](https://sugi.bio/atlas/gene/HRAS/) |
| Protein change (HGVS p.) | p.Glu76= |
| Coding change (HGVS c.) | c.228G>A |
| MANE Select transcript | [NM_198075](https://www.ncbi.nlm.nih.gov/nuccore/NM_198075) (variant reported on NM_005343) |
| dbSNP | [rs1057522598](https://www.ncbi.nlm.nih.gov/snp/rs1057522598/) |
| Variant type | single nucleotide variant |
| Location | chr11:533828-533828 (GRCh38) |
| ClinVar | [VCV386770](https://www.ncbi.nlm.nih.gov/clinvar/variation/386770/) |

**All HGVS expressions:** `LRG_506:g.6723G>A`, `LRG_506t1:c.228G>A`, `NC_000011.10:g.533828C>T`, `NC_000011.9:g.533828C>T`, `NG_007666.1:g.6723G>A`, `NM_001130442.3:c.228G>A`, `NM_001318054.2:c.-92G>A`, `NM_005343.4:c.228G>A`, `NM_176795.5:c.228G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.087, GERP -3.74, phastCons 0.918 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.383**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · 1/74,918 in the highest group · 2/1,613,282 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00133% | 74,918 |
| European (non-Finnish) | 8.47e-05% | 1,180,016 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-29.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2017–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2017-07-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-29 |

## Associated conditions {#conditions}

[Costello syndrome](https://sugi.bio/atlas/disease/costello-syndrome/).

**Reported phenotype names (ClinVar):** Costello syndrome, not provided, none provided, FACIOCUTANEOSKELETAL SYNDROME, FCS SYNDROME, HRAS-Related Costello Syndrome.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 386770). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*