# NM_001635.4(AMPH):c.532A>G (p.Lys178Glu)

https://sugi.bio/variant/amph-p-lys178glu

## Summary

**AMPH p.Lys178Glu (c.532A>G)** is classified **Uncertain significance** in AMPH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-25). AlphaMissense: likely pathogenic (0.8234); Ultra-rare (popmax 0.0167%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs199555769 · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0167%, amr)

## For patients & families {#patients}

This is a change in the AMPH gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [AMPH](https://sugi.bio/atlas/gene/AMPH/) |
| Protein change (HGVS p.) | p.Lys178Glu |
| Coding change (HGVS c.) | c.532A>G |
| MANE Select transcript | [NM_001635](https://www.ncbi.nlm.nih.gov/nuccore/NM_001635) |
| dbSNP | [rs199555769](https://www.ncbi.nlm.nih.gov/snp/rs199555769/) |
| Variant type | single nucleotide variant |
| Location | chr7:38475389-38475389 (GRCh38) |
| ClinVar | [VCV3116989](https://www.ncbi.nlm.nih.gov/clinvar/variation/3116989/) |

**All HGVS expressions:** `NC_000007.13:g.38514989T>C`, `NC_000007.14:g.38475389T>C`, `NG_230097.1:g.307T>C`, `NM_001635.4:c.532A>G`, `NM_139316.3:c.532A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.8234)
- REVEL 0.292 (indeterminate)
- SaProt LLR -12.808 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 7.879, GERP 1.86, phastCons 1 — highly conserved (agrees)
- 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 0.71** across the covering region of the MANE Select transcript (38,465,510–38,631,351), spanning 165,841 bp. Chi-square p 1e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.34 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0167%** (amr) · FAF95 0.009% · FAF99 0.00682% · 10/59,962 in the highest group · 56/1,613,044 alleles overall — ultra-rare (popmax 0.0167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0167% | 5,996 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,819 |
| European (non-Finnish) | 0.00365% | 27,429 |

*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}

**AMPH** population constraint: LOEUF 0.697, pLI 1.6051e-06, missense-Z 1.1391. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **178** lies in the bar domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 64.84, 39% of residues very-high.

**6 experimental structure(s)** (PDB): [1KY7](https://www.rcsb.org/structure/1KY7), [1UTC](https://www.rcsb.org/structure/1UTC), [3SOG](https://www.rcsb.org/structure/3SOG), [4ATM](https://www.rcsb.org/structure/4ATM), [5M5S](https://www.rcsb.org/structure/5M5S), [5M61](https://www.rcsb.org/structure/5M61).

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

*Describes the biological roles of AMPH (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:** AMPH's established molecular role includes phospholipid binding. p.Lys178Glu falls in the bar domain.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |

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

**Molecular function:** phospholipid binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-25.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-25 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related AMPH variant pages (same residue, condition, or type): [AMPH c.1017+10T>C](/variant/amph-c-1017-plus-10t-c), [AMPH p.Thr586Met](/variant/amph-p-thr586met), [AMPH p.Ala10Thr](/variant/amph-p-ala10thr), [AMPH p.Ala169Gly](/variant/amph-p-ala169gly), [AMPH p.Ala239Ser](/variant/amph-p-ala239ser), [AMPH p.Ala248Val](/variant/amph-p-ala248val), [AMPH p.Ala284Val](/variant/amph-p-ala284val), [AMPH p.Ala287Thr](/variant/amph-p-ala287thr).

### 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 3116989). 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.*