# NM_001378454.1(ALMS1):c.6415C>T (p.Pro2139Ser)

https://sugi.bio/variant/alms1-p-pro2139ser

## Summary

**ALMS1 p.Pro2139Ser (c.6415C>T)** is classified **Conflicting classifications of pathogenicity** in ALMS1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-25). AlphaMissense: likely benign (0.1039); Very rare (popmax 0.00186%, nfe); Associated with Alstrom syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs772858451 · 3 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00186%, nfe)

## For patients & families {#patients}

This is a change in the ALMS1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to Alstrom syndrome.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ALMS1 is a diagnostic-grade gene on 21 Genomics England panels |

**Commonly reported features of Alström syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Otitis media — Very frequent (99-80%)
- Progressive sensorineural hearing impairment — Very frequent (99-80%)
- Cone/cone-rod dystrophy — Very frequent (99-80%)
- Retinal dystrophy — Very frequent (99-80%)
- Visual loss — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)
- Insulin resistance — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005787/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALMS1](https://sugi.bio/atlas/gene/ALMS1/) |
| Protein change (HGVS p.) | p.Pro2139Ser |
| Coding change (HGVS c.) | c.6415C>T |
| MANE Select transcript | [NM_001378454](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378454) |
| dbSNP | [rs772858451](https://www.ncbi.nlm.nih.gov/snp/rs772858451/) |
| Variant type | single nucleotide variant |
| Location | chr2:73452942-73452942 (GRCh38) |
| ClinVar | [VCV1310250](https://www.ncbi.nlm.nih.gov/clinvar/variation/1310250/) |

**All HGVS expressions:** `LRG_741:g.72190C>T`, `LRG_741t1:c.6418C>T`, `NC_000002.11:g.73680069C>T`, `NC_000002.12:g.73452942C>T`, `NG_011690.1:g.72190C>T`, `NM_001378454.1:c.6415C>T`, `NM_015120.4:c.6418C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1039)
- REVEL 0.009 (strongly benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP -1, GERP -2.77 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 0.015**. 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 1.12** across the covering region of the MANE Select transcript (73,385,869–73,609,609), spanning 223,740 bp. Chi-square p 1.9e-16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for ALMS1 (1,677 scored positions, the nearest 105 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00186%** (nfe) · FAF95 0.00122% · FAF99 0.00104% · 22/1,179,764 in the highest group · 26/1,613,286 alleles overall — very rare (popmax 0.00186%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,231 |
| European (non-Finnish) (grpmax) | 0.00186% | 53,626 |
| Admixed American | 0.00167% | 59,950 |
| South Asian | 0.0011% | 91,038 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**ALMS1** population constraint: LOEUF 0.825, pLI 2.1295e-65, missense-Z -1.692; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Alstrom syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **2139** lies in the '34 x 47 aa approximate tandem repeat' region.

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

*Describes the biological roles of ALMS1 (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}

ALMS1 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | curated |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | curated |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | curated |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |

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

**Biological process:** endosomal transport, regulation of stress fiber assembly.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-07-25.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely benign).

**Submission history:** 3 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-11-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-16 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-25 |

## Associated conditions {#conditions}

[Alstrom syndrome](https://sugi.bio/atlas/disease/alstrom-syndrome/).

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

## Similar variants {#similar}

Related ALMS1 variant pages (same residue, condition, or type): [ALMS1 c.10079-1G>C](/variant/alms1-c-10079-minus-1g-c), [ALMS1 c.10214-2A>G](/variant/alms1-c-10214-minus-2a-g), [ALMS1 c.10384+1G>A](/variant/alms1-c-10384-plus-1g-a), [ALMS1 c.10385-2A>G](/variant/alms1-c-10385-minus-2a-g), [ALMS1 c.11547+3A>T](/variant/alms1-c-11547-plus-3a-t), [ALMS1 c.11668+1G>T](/variant/alms1-c-11668-plus-1g-t), [ALMS1 c.11669-1G>A](/variant/alms1-c-11669-minus-1g-a), [ALMS1 c.11669-1G>C](/variant/alms1-c-11669-minus-1g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1310250). 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.*