# NM_000477.7(ALB):c.528G>A (p.Pro176=)

https://sugi.bio/variant/alb-p-pro176

## Summary

**ALB p.Pro176= (c.528G>A)** is classified **Likely benign** in ALB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). Ultra-rare (popmax 0.0253%, afr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0253%, afr)

## For patients & families {#patients}

This is a change in the ALB 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 | [ALB](https://sugi.bio/atlas/gene/ALB/) |
| Protein change (HGVS p.) | p.Pro176= |
| Coding change (HGVS c.) | c.528G>A |
| MANE Select transcript | [NM_000477](https://www.ncbi.nlm.nih.gov/nuccore/NM_000477) |
| Variant type | single nucleotide variant |
| Location | chr4:73409400-73409400 (GRCh38) |
| ClinVar | [VCV4738834](https://www.ncbi.nlm.nih.gov/clinvar/variation/4738834/) |

**All HGVS expressions:** `NC_000004.11:g.74275117G>A`, `NC_000004.12:g.73409400G>A`, `NG_009291.1:g.10146G>A`, `NM_000477.7:c.528G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.26) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.508, GERP -0.693 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.035**. 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 deltas (raw): acceptor loss **0.02**, donor loss **0.26**, acceptor gain **0.02**, donor gain **0.00**. Largest is donor loss, 23 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0253%** (afr) · FAF95 0.0166% · FAF99 0.0137% · 19/74,988 in the highest group · 35/1,613,824 alleles overall — ultra-rare (popmax 0.0253%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0253% | 3,947 |
| South Asian | 0.00439% | 22,763 |
| Admixed American | 0.00333% | 30,000 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,494 |
| European (non-Finnish) | 0.000763% | 131,094 |

*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):

- **hyperthyroxinemia, familial dysalbuminemic** — Moderate (AD)
- **congenital analbuminemia** — Definitive (AR)

## Protein context {#protein}

Residue **176** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 64.11, 33% of residues very-high.

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

*Describes the biological roles of ALB (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.*


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |

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

**Biological process:** apical junction assembly, cilium assembly, establishment of epithelial cell polarity.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-21.

**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 | 2025-08-21 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ALB variant pages (same residue, condition, or type): [ALB p.Pro176Leu](/variant/alb-p-pro176leu), [ALB p.Arg138Ter](/variant/alb-p-arg138ter), [ALB p.Ala324Pro](/variant/alb-p-ala324pro), [ALB p.Ala387Ser](/variant/alb-p-ala387ser), [ALB p.Ala83Gly](/variant/alb-p-ala83gly), [ALB p.Arg105His](/variant/alb-p-arg105his), [ALB p.Arg23Cys](/variant/alb-p-arg23cys), [ALB p.Asp197Tyr](/variant/alb-p-asp197tyr).

### 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 4738834). 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.*