# NM_000371.4(TTR):c.130C>T (p.Pro44Ser)

https://sugi.bio/variant/ttr-p-pro44ser

## Summary

**TTR p.Pro44Ser (c.130C>T)** is classified **Pathogenic/Likely pathogenic** in TTR (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-13). AlphaMissense: ambiguous (0.4862); Very rare (popmax 8.47e-05%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs11541790 · 7 submitters · 2 linked conditions · AlphaMissense ambiguous · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the TTR gene that is considered likely disease-causing, submitted by 7 submitters, and is linked to Cardiovascular phenotype.

*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 | [TTR](https://sugi.bio/atlas/gene/TTR/) |
| Protein change (HGVS p.) | p.Pro44Ser |
| Coding change (HGVS c.) | c.130C>T |
| MANE Select transcript | [NM_000371](https://www.ncbi.nlm.nih.gov/nuccore/NM_000371) |
| dbSNP | [rs11541790](https://www.ncbi.nlm.nih.gov/snp/rs11541790/) |
| Variant type | single nucleotide variant |
| Location | chr18:31592956-31592956 (GRCh38) |
| ClinVar | [VCV181693](https://www.ncbi.nlm.nih.gov/clinvar/variation/181693/) |

**All HGVS expressions:** `LRG_416:g.6190C>T`, `LRG_416t1:c.130C>T`, `NC_000018.10:g.31592956C>T`, `NC_000018.9:g.29172919C>T`, `NG_009490.1:g.6190C>T`, `NM_000371.4:c.130C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.4862) — no call either way
- REVEL 0.955 (strongly pathogenic-leaning)
- SaProt LLR -7.909 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate
- Conservation: phyloP 7.692, GERP 1.78, phastCons 1 — highly conserved
- CADD: **PHRED 24.9**. 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 0.73** across the covering region of the MANE Select transcript (31,591,903–31,598,672), spanning 6,769 bp. Chi-square p 0.00021. 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 **8.47e-05%** (nfe) · 1/1,179,988 in the highest group · 1/1,614,026 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}

**TTR** population constraint: LOEUF 1.049, pLI 0.01296, missense-Z 1.5504; ClinGen dosage — haploinsufficiency 0/3, 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):

- **obsolete hereditary ATTR amyloidosis** — Definitive (AD)

## Protein context {#protein}

Residue **44** lies in a UniProt-annotated variant site (in amyld1; amyloid polyneuropathy).

AlphaFold model confidence (whole protein): pLDDT 88.74, 79% of residues very-high.

**493 experimental structure(s)** (PDB): [1BM7](https://www.rcsb.org/structure/1BM7), [1BMZ](https://www.rcsb.org/structure/1BMZ), [1BZ8](https://www.rcsb.org/structure/1BZ8), [1BZD](https://www.rcsb.org/structure/1BZD), [1BZE](https://www.rcsb.org/structure/1BZE), [1DVQ](https://www.rcsb.org/structure/1DVQ) — incl. mutant structure 1BZD.

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

*Describes the biological roles of TTR (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:** TTR's established molecular role includes identical protein binding. In Reactome, TTR is annotated in disease pathway(s) including **Defective visual phototransduction due to STRA6 loss of function**.

**Disease mechanism (Reactome):** TTR loss or alteration is curated in [Defective visual phototransduction due to STRA6 loss of function](https://reactome.org/content/detail/R-HSA-9918449).

### Pathways affected {#pathways}

TTR participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective visual phototransduction due to STRA6 loss of function](https://reactome.org/content/detail/R-HSA-9918449) | curated |
| [Amyloid fiber formation](https://reactome.org/content/detail/R-HSA-977225) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Non-integrin membrane-ECM interactions](https://reactome.org/content/detail/R-HSA-3000171) | curated |
| [Retinoid metabolism and transport](https://reactome.org/content/detail/R-HSA-975634) | curated |
| [The canonical retinoid cycle in rods (twilight vision)](https://reactome.org/content/detail/R-HSA-2453902) | curated |

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

**Molecular function:** identical protein binding.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-13.

**Submitter consensus:** conflicting (6 Pathogenic, 1 Likely pathogenic).

**Submission history:** 7 submissions (2014–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-21 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-19 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-19 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-17 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-13 |
| Stanford Center for Inherited Cardiovascular Disease, Stanford University | Likely pathogenic | criteria provided, single submitter | provider interpretation | 2014-02-10 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [amyloidosis, hereditary systemic 1](https://sugi.bio/atlas/disease/amyloidosis-hereditary-systemic-1/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not provided, Amyloidosis, hereditary systemic 1, none provided, Hereditary Transthyretin Amyloidosis, Isolated Cardiac Amyloidosis, Amyloid Cardiomyopathy, Transthyretin-related, Transthyretin Amyloidosis, Hereditary oculoleptomeningeal amyloid angiopathy, Familial Transthyretin Amyloidosis.

## Same-residue context {#hotspot}

Residue **44** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TTR p.Pro44Leu](/variant/ttr-p-pro44leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TTR variant pages (same residue, condition, or type): [TTR p.Pro44Leu](/variant/ttr-p-pro44leu), [TTR p.Ala117Ser](/variant/ttr-p-ala117ser), [TTR p.Ala39Asp](/variant/ttr-p-ala39asp), [TTR p.Ala56Pro](/variant/ttr-p-ala56pro), [TTR p.Ala65Asp](/variant/ttr-p-ala65asp), [TTR p.Ala65Thr](/variant/ttr-p-ala65thr), [TTR p.Ala65Val](/variant/ttr-p-ala65val), [TTR p.Arg54Thr](/variant/ttr-p-arg54thr).

### 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 181693). 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.*