# NM_001635.4(AMPH):c.142C>T (p.Arg48Trp)

https://sugi.bio/variant/amph-p-arg48trp

## Summary

**AMPH p.Arg48Trp (c.142C>T)** is classified **Likely benign** in AMPH (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-06). AlphaMissense: likely pathogenic (0.8976); Rare (popmax 0.256%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs147234401 · 1 submitter · AlphaMissense likely pathogenic · rare (popmax 0.256%, nfe)

## For patients & families {#patients}

This is a change in the AMPH 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 | [AMPH](https://sugi.bio/atlas/gene/AMPH/) |
| Protein change (HGVS p.) | p.Arg48Trp |
| Coding change (HGVS c.) | c.142C>T |
| MANE Select transcript | [NM_001635](https://www.ncbi.nlm.nih.gov/nuccore/NM_001635) |
| dbSNP | [rs147234401](https://www.ncbi.nlm.nih.gov/snp/rs147234401/) |
| Variant type | single nucleotide variant |
| Location | chr7:38534939-38534939 (GRCh38) |
| ClinVar | [VCV722907](https://www.ncbi.nlm.nih.gov/clinvar/variation/722907/) |

**All HGVS expressions:** `NC_000007.13:g.38574539G>A`, `NC_000007.14:g.38534939G>A`, `NM_001635.4:c.142C>T`, `NM_139316.3:c.142C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8976)
- REVEL 0.362 (indeterminate)
- SaProt LLR -15.157 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 1.854, GERP -3.71, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 25.6**. 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 (G>T, Δ0.25 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 **0.256%** (nfe) · FAF95 0.248% · FAF99 0.245% · 3,021/1,179,742 in the highest group · 3,208/1,613,644 alleles overall — rare (popmax 0.256%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.256% | 391 |
| Remaining individuals (not grpmax-eligible) | 0.123% | 812 |
| Admixed American | 0.07% | 1,428 |
| Middle Eastern | 0.0495% | 2,020 |
| African / African-American | 0.0427% | 2,343 |
| Finnish (not grpmax-eligible) | 0.025% | 3,998 |
| South Asian | 0.0165% | 6,068 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,600 |
| East Asian | 0.00223% | 44,858 |

*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 **48** 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.Arg48Trp 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-08-06.

**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 | 2018-08-06 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## 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 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 722907). 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.*