# NM_000032.5(ALAS2):c.351C>T (p.Ser117=)

https://sugi.bio/variant/alas2-p-ser117

## Summary

**ALAS2 p.Ser117= (c.351C>T)** is classified **Likely benign** in ALAS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-05). Very rare (popmax 0.00438%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs935422541 · 1 submitter · very rare (popmax 0.00438%, amr)

## For patients & families {#patients}

This is a change in the ALAS2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALAS2](https://sugi.bio/atlas/gene/ALAS2/) |
| Protein change (HGVS p.) | p.Ser117= |
| Coding change (HGVS c.) | c.351C>T |
| MANE Select transcript | [NM_000032](https://www.ncbi.nlm.nih.gov/nuccore/NM_000032) |
| dbSNP | [rs935422541](https://www.ncbi.nlm.nih.gov/snp/rs935422541/) |
| Variant type | single nucleotide variant |
| Location | chrX:55023821-55023821 (GRCh38) |
| ClinVar | [VCV2893480](https://www.ncbi.nlm.nih.gov/clinvar/variation/2893480/) |

**All HGVS expressions:** `LRG_1163:g.12244C>T`, `LRG_1163t1:c.351C>T`, `NC_000023.10:g.55050254G>A`, `NC_000023.11:g.55023821G>A`, `NG_008983.1:g.12244C>T`, `NG_051542.1:g.165G>A`, `NM_000032.5:c.351C>T`, `NM_001037967.4:c.304+897C>T`, `NM_001037968.4:c.376+897C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.86, GERP -2.49, phastCons 0.001 — weakly conserved position
- CADD: **PHRED 2.301**. 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 deltas (raw): acceptor loss **0.22**, donor loss **0.00**, acceptor gain **0.13**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.22**, donor loss **0.00**, acceptor gain **0.13**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00438%** (amr) · FAF95 0.000726% · FAF99 0.000272% · 2/45,645 in the highest group · 5/1,208,951 alleles overall — very rare (popmax 0.00438%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00438% | 22,823 |
| European (non-Finnish) | 0.000335% | 298,318 |

*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.*

## Gene constraint & dosage {#gene-context}


Curated gene–disease validity (ClinGen):

- **X-linked erythropoietic protoporphyria** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.76, 71% of residues very-high.

**27 experimental structure(s)** (PDB): [5QQQ](https://www.rcsb.org/structure/5QQQ), [5QQR](https://www.rcsb.org/structure/5QQR), [5QQS](https://www.rcsb.org/structure/5QQS), [5QQT](https://www.rcsb.org/structure/5QQT), [5QQU](https://www.rcsb.org/structure/5QQU), [5QQV](https://www.rcsb.org/structure/5QQV).

## What this gene does {#gene-function}

*Describes the biological roles of ALAS2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ALAS2's established molecular role includes 5-aminolevulinate synthase activity.


### Pathways affected {#pathways}

ALAS2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Heme biosynthesis](https://reactome.org/content/detail/R-HSA-189451) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** 5-aminolevulinate synthase activity.

**Biological process:** response to hypoxia, obsolete protoporphyrinogen IX biosynthetic process, heme B biosynthetic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-05.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-05 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ALAS2 variant pages (same residue, condition, or type): [ALAS2 p.Arg170Cys](/variant/alas2-p-arg170cys), [ALAS2 p.Arg411Cys](/variant/alas2-p-arg411cys), [ALAS2 p.Arg452Cys](/variant/alas2-p-arg452cys), [ALAS2 p.Arg452His](/variant/alas2-p-arg452his), [ALAS2 p.Arg452Ser](/variant/alas2-p-arg452ser), [ALAS2 c.1168+4A>C](/variant/alas2-c-1168-plus-4a-c), [ALAS2 p.Ala282Thr](/variant/alas2-p-ala282thr), [ALAS2 p.Ala336Asp](/variant/alas2-p-ala336asp).

### 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 2893480). 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.*