# NM_001378454.1(ALMS1):c.4988C>T (p.Thr1663Ile)

https://sugi.bio/variant/alms1-p-thr1663ile

## Summary

**ALMS1 p.Thr1663Ile (c.4988C>T)** is classified **Conflicting classifications of pathogenicity** in ALMS1 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.106); Rare (popmax 0.916%, afr); Associated with monogenic diabetes.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs188807564 · 12 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.916%, afr)

## 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 12 submitters, and is linked to monogenic diabetes.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [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.Thr1663Ile |
| Coding change (HGVS c.) | c.4988C>T |
| MANE Select transcript | [NM_001378454](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378454) |
| dbSNP | [rs188807564](https://www.ncbi.nlm.nih.gov/snp/rs188807564/) |
| Variant type | single nucleotide variant |
| Location | chr2:73451515-73451515 (GRCh38) |
| ClinVar | [VCV241000](https://www.ncbi.nlm.nih.gov/clinvar/variation/241000/) |

**All HGVS expressions:** `LRG_741:g.70763C>T`, `LRG_741t1:c.4991C>T`, `NC_000002.11:g.73678642C>T`, `NC_000002.12:g.73451515C>T`, `NG_011690.1:g.70763C>T`, `NM_001378454.1:c.4988C>T`, `NM_015120.4:c.4991C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.106)
- REVEL 0.008 (strongly benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP -20, GERP -4.1 — fast-evolving / accelerated position
- **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 0.005**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.916%** (afr) · FAF95 0.859% · FAF99 0.836% · 686/74,910 in the highest group · 743/1,613,754 alleles overall — rare (popmax 0.916%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.916% | 109 |
| Remaining individuals (not grpmax-eligible) | 0.0496% | 2,016 |
| Admixed American | 0.03% | 3,333 |
| Middle Eastern | 0.0165% | 6,060 |
| European (non-Finnish) | 0.000593% | 168,556 |

*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 **1663** 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 2026-01-29.

**Submitter consensus:** conflicting (9 Likely benign, 1 Benign, 1 Uncertain significance, 1 Likely Benign).

**Submission history:** 12 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2016-03-14 |
| Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Likely benign | criteria provided, single submitter | research | 2017-11-10 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2018-12-29 |
| Eurofins Ntd Llc (ga) | Likely benign | criteria provided, single submitter | clinical testing | 2018-07-31 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-08 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2016-03-21 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2019-08-14 |
| Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | Uncertain significance | criteria provided, single submitter | research |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-06-12 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely Benign | criteria provided, single submitter | clinical testing | 2024-05-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-29 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-02-01 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related ALMS1 variant pages (same residue, condition, or type): [ALMS1 p.Thr1663Pro](/variant/alms1-p-thr1663pro), [ALMS1 p.Thr1663Ala](/variant/alms1-p-thr1663ala), [ALMS1 p.Thr1663=](/variant/alms1-p-thr1663), [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).

### 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 241000). 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.*