# NM_000095.3(COMP):c.410T>C (p.Phe137Ser)

https://sugi.bio/variant/comp-p-phe137ser

## Summary

**COMP p.Phe137Ser (c.410T>C)** is classified **Benign/Likely benign** in COMP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-02). AlphaMissense: likely pathogenic (0.6326); Ultra-rare (popmax 0.0257%, nfe); Associated with connective tissue disorder.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs757094319 · 4 submitters · 3 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0257%, nfe)

## For patients & families {#patients}

This is a change in the COMP gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters, and is linked to connective tissue disorder.

*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 | 83 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COMP](https://sugi.bio/atlas/gene/COMP/) |
| Protein change (HGVS p.) | p.Phe137Ser |
| Coding change (HGVS c.) | c.410T>C |
| MANE Select transcript | [NM_000095](https://www.ncbi.nlm.nih.gov/nuccore/NM_000095) |
| dbSNP | [rs757094319](https://www.ncbi.nlm.nih.gov/snp/rs757094319/) |
| Variant type | single nucleotide variant |
| Location | chr19:18789278-18789278 (GRCh38) |
| ClinVar | [VCV328623](https://www.ncbi.nlm.nih.gov/clinvar/variation/328623/) |

**All HGVS expressions:** `NC_000019.10:g.18789278A>G`, `NC_000019.9:g.18900087A>G`, `NG_007070.1:g.7028T>C`, `NM_000095.3:c.410T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6326)
- REVEL 0.128 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -9.117 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 4.884, GERP 2.02, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.8**. 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 0.84** across the covering region of the MANE Select transcript (18,782,918–18,791,269), spanning 8,351 bp. Chi-square p 2.2e-07. 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 **0.0257%** (nfe) · FAF95 0.0232% · FAF99 0.0223% · 290/1,128,244 in the highest group · 304/1,500,312 alleles overall — ultra-rare (popmax 0.0257%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0257% | 3,890 |
| Remaining individuals (not grpmax-eligible) | 0.0191% | 5,225 |
| Admixed American | 0.00731% | 13,678 |

*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}

**COMP** population constraint: LOEUF 1.073, pLI 1.6355e-24, missense-Z 1.5119; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *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):

- **COMP-related skeletal dysplasia** — Definitive (AD)

## Protein context {#protein}

Residue **137** lies in the egf-like 2; calcium-binding domain; a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 88.60, 67% of residues very-high.

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

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

*Describes the biological roles of COMP (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:** COMP's established molecular role includes protease binding. p.Phe137Ser falls in the egf-like 2; calcium-binding domain.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |

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

**Molecular function:** protease binding, calcium ion binding, collagen binding, heparin binding, proteoglycan binding, heparan sulfate proteoglycan binding.

**Biological process:** negative regulation of apoptotic process, protein homooligomerization, limb development, cartilage homeostasis.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-02.

**Submitter consensus:** conflicting (4 Likely benign, 1 Benign).

**Submission history:** 5 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Benign | criteria provided, single submitter | clinical testing | 2020-03-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-02 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-10 |

## Associated conditions {#conditions}

[connective tissue disorder](https://sugi.bio/atlas/disease/connective-tissue-disorder/), [multiple epiphyseal dysplasia type 1](https://sugi.bio/atlas/disease/multiple-epiphyseal-dysplasia-type-1/), [pseudoachondroplasia](https://sugi.bio/atlas/disease/pseudoachondroplasia/).

**Reported phenotype names (ClinVar):** Connective tissue disorder, Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome, Multiple epiphyseal dysplasia type 1, not provided, not specified, AllHighlyPenetrant, none provided, Connective tissue disease, COMP-Related Multiple Epiphyseal Dysplasia, PSEUDOACHONDROPLASTIC DYSPLASIA.

## Similar variants {#similar}

Related COMP variant pages (same residue, condition, or type): [COMP p.Phe137=](/variant/comp-p-phe137), [COMP p.Arg718Trp](/variant/comp-p-arg718trp), [COMP p.Asn489Lys](/variant/comp-p-asn489lys), [COMP p.Asn523Lys](/variant/comp-p-asn523lys), [COMP p.Asn555Lys](/variant/comp-p-asn555lys), [COMP p.Asp269Gly](/variant/comp-p-asp269gly), [COMP p.Asp273Val](/variant/comp-p-asp273val), [COMP p.Asp326Asn](/variant/comp-p-asp326asn).

### 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 328623). 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.*