# NM_000032.5(ALAS2):c.514G>A (p.Ala172Thr)

https://sugi.bio/variant/alas2-p-ala172thr

## Summary

**ALAS2 p.Ala172Thr (c.514G>A)** is classified **Conflicting classifications of pathogenicity** in ALAS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-04). AlphaMissense: likely benign (0.3045); Very rare (popmax 0.00134%, nfe); Associated with X-linked sideroblastic anemia 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs137852304 · 3 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00134%, nfe)

## For patients & families {#patients}

This is a change in the ALAS2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to X-linked sideroblastic anemia 1.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | X-linked recessive |
| Age of onset (of this condition) | All ages |
| Diagnostic panels | ALAS2 is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of X-linked sideroblastic anemia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Pallor — Very frequent (99-80%)
- Muscle weakness — Very frequent (99-80%)
- Anemia — Very frequent (99-80%)
- Abnormality of iron homeostasis — Very frequent (99-80%)
- Fatigue — Very frequent (99-80%)
- Hyperpigmentation of the skin — Occasional (29-5%)
- Splenomegaly — Occasional (29-5%)
- Glucose intolerance — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009456/index) · [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.Ala172Thr |
| Coding change (HGVS c.) | c.514G>A |
| MANE Select transcript | [NM_000032](https://www.ncbi.nlm.nih.gov/nuccore/NM_000032) |
| dbSNP | [rs137852304](https://www.ncbi.nlm.nih.gov/snp/rs137852304/) |
| Variant type | single nucleotide variant |
| Location | chrX:55021176-55021176 (GRCh38) |
| ClinVar | [VCV10473](https://www.ncbi.nlm.nih.gov/clinvar/variation/10473/) |

**All HGVS expressions:** `LRG_1163:g.14889G>A`, `LRG_1163t1:c.514G>A`, `NC_000023.10:g.55047609C>T`, `NC_000023.11:g.55021176C>T`, `NG_008983.1:g.14889G>A`, `NM_000032.5:c.514G>A`, `NM_001037967.4:c.403G>A`, `NM_001037968.4:c.475G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3045)
- REVEL 0.956 (strongly pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -8.516 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 7.606, GERP 1.87, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.5**. 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.*
- Regional missense constraint: **o/e 0.52** across the covering region of the MANE Select transcript (55,014,867–55,023,840), spanning 8,973 bp. Chi-square p 5.5e-15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00134%** (nfe) · FAF95 0.000715% · FAF99 0.000564% · 12/895,239 in the highest group · 12/1,097,883 alleles overall — very rare (popmax 0.00134%, nfe).

*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}

Residue **172** lies in an α-helix.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-08-04.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 3 submissions (1995–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1995-10-01 |
| Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-10-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-04 |

## Associated conditions {#conditions}

[X-linked sideroblastic anemia 1](https://sugi.bio/atlas/disease/x-linked-sideroblastic-anemia-1/).

**Reported phenotype names (ClinVar):** X-linked sideroblastic anemia 1, Sideroblastic anemia 1, late-onset, not provided, none provided, Anemia, hereditary sideroblastic, late-onset, Erythroid 5-aminolevulinate synthase deficiency, X chromosome-linked sideroblastic anemia, ANEMIA, SIDEROBLASTIC, 1, PYRIDOXINE REFRACTORY, X-linked pyridoxine-refractory sideroblastic anemia, Anemia, sideroblastic, 1.

## Similar variants {#similar}

Related ALAS2 variant pages (same residue, condition, or type): [ALAS2 p.Arg411Cys](/variant/alas2-p-arg411cys), [ALAS2 p.Arg452Cys](/variant/alas2-p-arg452cys), [ALAS2 p.Ala336Asp](/variant/alas2-p-ala336asp), [ALAS2 p.Cys471Arg](/variant/alas2-p-cys471arg), [ALAS2 c.824-15C>T](/variant/alas2-c-824-minus-15c-t), [ALAS2 c.*124C>T](/variant/alas2-c-star-124c-t), [ALAS2 c.*56A>C](/variant/alas2-c-star-56a-c), [ALAS2 p.Ala542=](/variant/alas2-p-ala542).

### 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 10473). 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.*