# NM_004752.4(GCM2):c.307C>T (p.Pro103Ser)

https://sugi.bio/variant/gcm2-p-pro103ser

## Summary

**GCM2 p.Pro103Ser (c.307C>T)** is classified **Uncertain significance** in GCM2 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-07-15). AlphaMissense: likely pathogenic (0.9969); Absent from gnomAD v4.1; Associated with hyperparathyroidism 4.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1561672362 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GCM2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to hyperparathyroidism 4.

*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 dominant |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | GCM2 is a diagnostic-grade gene on 2 Genomics England panels |

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

- Nephrocalcinosis — Very frequent (99-80%)
- Chondrocalcinosis — Very frequent (99-80%)
- Osteopenia — Very frequent (99-80%)
- Hypophosphatemia — Very frequent (99-80%)
- Hypercalciuria — Very frequent (99-80%)
- Parathyroid adenoma — Very frequent (99-80%)
- Hypercalcemia — Very frequent (99-80%)
- Hyperphosphaturia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018256/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GCM2](https://sugi.bio/atlas/gene/GCM2/) |
| Protein change (HGVS p.) | p.Pro103Ser |
| Coding change (HGVS c.) | c.307C>T |
| MANE Select transcript | [NM_004752](https://www.ncbi.nlm.nih.gov/nuccore/NM_004752) |
| dbSNP | [rs1561672362](https://www.ncbi.nlm.nih.gov/snp/rs1561672362/) |
| Variant type | single nucleotide variant |
| Location | chr6:10877176-10877176 (GRCh38) |
| ClinVar | [VCV591144](https://www.ncbi.nlm.nih.gov/clinvar/variation/591144/) |

**All HGVS expressions:** `NC_000006.11:g.10877409G>A`, `NC_000006.12:g.10877176G>A`, `NG_008970.1:g.9690C>T`, `NM_004752.4:c.307C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9969)
- REVEL 0.896 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.094 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor gain** (Δ 0.37) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.67, GERP 1.83, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in GCM2 (of 2,990 modeled).
- CADD: **PHRED 31.0**. 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 0.83** across the covering region of the MANE Select transcript (10,873,998–10,877,219), spanning 3,221 bp. Chi-square p 0.00012. 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 **0.07**, acceptor gain **0.00**, donor gain **0.37**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.37**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**GCM2** population constraint: LOEUF 1.205, pLI 6.7102e-06, missense-Z 1.9513. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **103** lies in a DNA-binding region.

AlphaFold model confidence (whole protein): pLDDT 58.78, 28% of residues very-high.

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

*Describes the biological roles of GCM2 (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:** GCM2's established molecular role includes DNA-binding transcription factor activity, RNA polymerase II-specific. p.Pro103Ser falls in a DNA-binding region.


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

**Molecular function:** DNA-binding transcription factor activity, RNA polymerase II-specific, sequence-specific DNA binding, sequence-specific double-stranded DNA binding.

**Biological process:** transcription by RNA polymerase II, intracellular calcium ion homeostasis, intracellular phosphate ion homeostasis, parathyroid gland development.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-15.

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

**Submission history:** 2 submissions (2018–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Gharavi Laboratory, Columbia University | Uncertain significance | no assertion criteria provided | research | 2018-09-16 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-15 |

## Associated conditions {#conditions}

[hyperparathyroidism 4](https://sugi.bio/atlas/disease/hyperparathyroidism-4/), [hypoparathyroidism, familial isolated, 2](https://sugi.bio/atlas/disease/hypoparathyroidism-familial-isolated-2/).

**Reported phenotype names (ClinVar):** Hyperparathyroidism 4, not provided, Hypoparathyroidism, familial isolated, 2, none provided.

## Similar variants {#similar}

Related GCM2 variant pages (same residue, condition, or type): [GCM2 p.Arg47Leu](/variant/gcm2-p-arg47leu), [GCM2 p.Arg67Cys](/variant/gcm2-p-arg67cys), [GCM2 p.Tyr136Ter](/variant/gcm2-p-tyr136ter), [GCM2 p.Ala148Val](/variant/gcm2-p-ala148val), [GCM2 p.Ala180Pro](/variant/gcm2-p-ala180pro), [GCM2 p.Ala355Thr](/variant/gcm2-p-ala355thr), [GCM2 p.Ala451Val](/variant/gcm2-p-ala451val), [GCM2 p.Ala488Thr](/variant/gcm2-p-ala488thr).

### 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 591144). 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.*