# NM_001097577.3(ANG):c.99C>T (p.Phe33=)

https://sugi.bio/variant/ang-p-phe33

## Summary

**ANG p.Phe33= (c.99C>T)** is classified **Benign/Likely benign** in ANG (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-21). Rare (popmax 0.725%, sas); Associated with amyotrophic lateral sclerosis type 9.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs563139057 · 5 submitters · 1 linked condition · rare (popmax 0.725%, sas)

## For patients & families {#patients}

This is a change in the ANG gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to amyotrophic lateral sclerosis type 9.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010498/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ANG](https://sugi.bio/atlas/gene/ANG/) |
| Protein change (HGVS p.) | p.Phe33= |
| Coding change (HGVS c.) | c.99C>T |
| MANE Select transcript | [NM_002937](https://www.ncbi.nlm.nih.gov/nuccore/NM_002937) (variant reported on NM_001097577) |
| dbSNP | [rs563139057](https://www.ncbi.nlm.nih.gov/snp/rs563139057/) |
| Variant type | single nucleotide variant |
| Location | chr14:20693663-20693663 (GRCh38) |
| ClinVar | [VCV312773](https://www.ncbi.nlm.nih.gov/clinvar/variation/312773/) |

**All HGVS expressions:** `LRG_653:g.14487C>T`, `LRG_653t1:c.99C>T`, `NC_000014.8:g.21161822C>T`, `NC_000014.9:g.20693663C>T`, `NG_008717.2:g.14487C>T`, `NG_033053.1:g.14451C>T`, `NM_001097577.3:c.99C>T`, `NM_001145.4:c.99C>T`, `NM_001282192.2:c.-18+13C>T`, `NM_001282193.2:c.-17-5692C>T`, `NM_001385271.1:c.99C>T`, `NM_001385272.1:c.99C>T`, `NM_001385273.1:c.99C>T`, `NM_001385274.1:c.99C>T`, `NM_002937.5:c.-17-5692C>T`, `NM_194431.3:c.-18+4789C>T`, `NR_174964.1:n.553G>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 0.833, GERP 0.476, phastCons 1 — weakly conserved position
- CADD: **PHRED 12.86**. 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 **0.725%** (sas) · FAF95 0.679% · FAF99 0.661% · 660/91,082 in the highest group · 703/1,614,144 alleles overall — rare (popmax 0.725%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.725% | 138 |
| Remaining individuals (not grpmax-eligible) | 0.064% | 1,563 |
| Middle Eastern | 0.0165% | 6,062 |
| African / African-American | 0.00133% | 75,024 |
| European (non-Finnish) | 8.47e-05% | 1,180,026 |

*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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-21.

**Submitter consensus:** conflicting (3 Likely benign, 2 Benign).

**Submission history:** 5 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-03-15 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-04-19 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-21 |

## Associated conditions {#conditions}

[amyotrophic lateral sclerosis type 9](https://sugi.bio/atlas/disease/amyotrophic-lateral-sclerosis-type-9/).

**Reported phenotype names (ClinVar):** Amyotrophic lateral sclerosis type 9, not provided, Inborn genetic diseases, none provided.

### 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 312773). 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.*