# NM_000670.5(ADH4):c.260C>G (p.Pro87Arg)

https://sugi.bio/variant/adh4-p-pro87arg

## Summary

**ADH4 p.Pro87Arg (c.260C>G)** is classified **Uncertain significance** in ADH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.1937); Very rare (popmax 0.00306%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs376943095 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00306%, nfe)

## For patients & families {#patients}

This is a change in the ADH4 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 | [ADH4](https://sugi.bio/atlas/gene/ADH4/) |
| Protein change (HGVS p.) | p.Pro87Arg |
| Coding change (HGVS c.) | c.260C>G |
| MANE Select transcript | [NM_000670](https://www.ncbi.nlm.nih.gov/nuccore/NM_000670) |
| dbSNP | [rs376943095](https://www.ncbi.nlm.nih.gov/snp/rs376943095/) |
| Variant type | single nucleotide variant |
| Location | chr4:99141543-99141543 (GRCh38) |
| ClinVar | [VCV2210437](https://www.ncbi.nlm.nih.gov/clinvar/variation/2210437/) |

**All HGVS expressions:** `NC_000004.11:g.100062694G>C`, `NC_000004.12:g.99141543G>C`, `NM_000670.5:c.260C>G`, `NM_001306171.2:c.317C>G`, `NM_001306172.2:c.317C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1937)
- REVEL 0.313 (indeterminate)
- SaProt LLR -11.144 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 6.928, GERP 0.627, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.8**. 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 1.04** across the covering region of the MANE Select transcript (99,124,445–99,144,222), spanning 19,777 bp. Chi-square p 0.41. 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>A, Δ0.67 donor loss), 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 **0.00306%** (nfe) · FAF95 0.00224% · FAF99 0.00199% · 36/1,176,480 in the highest group · 37/1,604,538 alleles overall — very rare (popmax 0.00306%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00306% | 32,680 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,040 |

*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}

**ADH4** population constraint: LOEUF 1.077, pLI 1.8113e-06, missense-Z -0.24816. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 98.23, 99% of residues very-high.

**1 experimental structure(s)** (PDB): [3COS](https://www.rcsb.org/structure/3COS).

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

*Describes the biological roles of ADH4 (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:** ADH4's established molecular role includes alcohol dehydrogenase (NAD+) activity.


### Pathways affected {#pathways}

ADH4 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Ethanol oxidation](https://reactome.org/content/detail/R-HSA-71384) | curated |
| [RA biosynthesis pathway](https://reactome.org/content/detail/R-HSA-5365859) | curated |

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

**Molecular function:** alcohol dehydrogenase (NAD+) activity, all-trans-retinol dehydrogenase (NAD+) activity, all-trans retinal binding, zinc ion binding, benzaldehyde dehydrogenase (NAD+) activity, retinol binding.

**Biological process:** retinoid metabolic process, alcohol metabolic process, aldehyde metabolic process, fatty acid omega-oxidation, retinol metabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-13.

**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 | 2021-08-13 |

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

## Similar variants {#similar}

Related ADH4 variant pages (same residue, condition, or type): [ADH4 p.Ala15Thr](/variant/adh4-p-ala15thr), [ADH4 p.Ala188Val](/variant/adh4-p-ala188val), [ADH4 p.Ala222Thr](/variant/adh4-p-ala222thr), [ADH4 p.Ala290Thr](/variant/adh4-p-ala290thr), [ADH4 p.Ala62Pro](/variant/adh4-p-ala62pro), [ADH4 p.Ala72Val](/variant/adh4-p-ala72val), [ADH4 p.Arg318Cys](/variant/adh4-p-arg318cys), [ADH4 p.Arg318Leu](/variant/adh4-p-arg318leu).

### 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 2210437). 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.*