# NM_000095.3(COMP):c.1871C>T (p.Ala624Val)

https://sugi.bio/variant/comp-p-ala624val

## Summary

**COMP p.Ala624Val (c.1871C>T)** is classified **Uncertain significance** in COMP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-16). AlphaMissense: ambiguous (0.5327); Very rare (popmax 0.00383%, amr).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs201624503 · 2 submitters · AlphaMissense ambiguous · very rare (popmax 0.00383%, amr)

## For patients & families {#patients}

This is a change in the COMP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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 | [COMP](https://sugi.bio/atlas/gene/COMP/) |
| Protein change (HGVS p.) | p.Ala624Val |
| Coding change (HGVS c.) | c.1871C>T |
| MANE Select transcript | [NM_000095](https://www.ncbi.nlm.nih.gov/nuccore/NM_000095) |
| dbSNP | [rs201624503](https://www.ncbi.nlm.nih.gov/snp/rs201624503/) |
| Variant type | single nucleotide variant |
| Location | chr19:18784939-18784939 (GRCh38) |
| ClinVar | [VCV1429802](https://www.ncbi.nlm.nih.gov/clinvar/variation/1429802/) |

**All HGVS expressions:** `NC_000019.10:g.18784939G>A`, `NC_000019.9:g.18895749G>A`, `NG_007070.1:g.11366C>T`, `NM_000095.3:c.1871C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.5327) — no call either way
- REVEL 0.709 (pathogenic-leaning)
- SaProt LLR -10.137 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- SpliceAI predicts **donor gain** (Δ 0.98) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.802, GERP 2.02, phastCons 1 — highly conserved
- CADD: **PHRED 36.0**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.12**, acceptor gain **0.00**, donor gain **0.98**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.12**, acceptor gain **0.00**, donor gain **0.98**.
- Pangolin: Δ**0.61** (gain), gain 0.61 / loss 0.35. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00383%** (amr) · FAF95 0.000634% · FAF99 0.000237% · 2/52,282 in the highest group · 12/1,565,300 alleles overall — very rare (popmax 0.00383%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00383% | 26,141 |
| African / African-American | 0.00273% | 36,642 |
| Remaining individuals (not grpmax-eligible) | 0.00164% | 60,930 |
| South Asian | 0.00117% | 85,616 |
| European (non-Finnish) | 0.000517% | 193,398 |

*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 **624** lies in the tsp c-terminal domain; the 'mediates cell survival and induction of the iap family of survival proteins' region.

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.Ala624Val falls in the tsp c-terminal 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-16.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-11-22 |
| Dasa | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-16 |

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

## Similar variants {#similar}

Related COMP variant pages (same residue, condition, or type): [COMP p.Ala624=](/variant/comp-p-ala624), [COMP p.Ala624Thr](/variant/comp-p-ala624thr), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1429802). 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.*