# NM_000303.3(PMM2):c.621T>C (p.Phe207=)

https://sugi.bio/variant/pmm2-p-phe207

## Summary

**PMM2 p.Phe207= (c.621T>C)** is classified **Likely benign** in PMM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-15). Very rare (popmax 0.0033%, sas); Associated with PMM2-congenital disorder of glycosylation.

**At a glance:** Likely benign · review: Single submitter · rsID rs767491789 · 1 submitter · 1 linked condition · very rare (popmax 0.0033%, sas)

## For patients & families {#patients}

This is a change in the PMM2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to PMM2-congenital disorder of glycosylation.

*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 recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Italy) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PMM2 is a diagnostic-grade gene on 25 Genomics England panels |

**Commonly reported features of PMM2-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- High palate — Very frequent (99-80%)
- Strabismus — Very frequent (99-80%)
- Upslanted palpebral fissure — Very frequent (99-80%)
- Joint hypermobility — Frequent (79-30%)
- Wide mouth — Frequent (79-30%)
- Thin upper lip vermilion — Frequent (79-30%)
- Long face — Frequent (79-30%)
- Retrognathia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009826/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PMM2](https://sugi.bio/atlas/gene/PMM2/) |
| Protein change (HGVS p.) | p.Phe207= |
| Coding change (HGVS c.) | c.621T>C |
| MANE Select transcript | [NM_000303](https://www.ncbi.nlm.nih.gov/nuccore/NM_000303) |
| dbSNP | [rs767491789](https://www.ncbi.nlm.nih.gov/snp/rs767491789/) |
| Variant type | single nucleotide variant |
| Location | chr16:8813088-8813088 (GRCh38) |
| ClinVar | [VCV2982366](https://www.ncbi.nlm.nih.gov/clinvar/variation/2982366/) |

**All HGVS expressions:** `NC_000016.10:g.8813088T>C`, `NC_000016.9:g.8906945T>C`, `NG_009209.1:g.20276T>C`, `NM_000303.3:c.621T>C`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -3.9, GERP -4.16 — fast-evolving / accelerated position
- CADD: **PHRED 3.083**. 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.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for PMM2 (594 scored positions, the nearest 19 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0033%** (sas) · FAF95 0.000877% · FAF99 0.000443% · 3/90,820 in the highest group · 3/1,602,548 alleles overall — very rare (popmax 0.0033%, sas).

*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}

**PMM2** population constraint: LOEUF 1.937, pLI 5.5214e-08, missense-Z -1.8037; 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):

- **hyperinsulinemic hypoglycemia with polycystic kidney disease** — Moderate (AR)
- **PMM2-congenital disorder of glycosylation** — Definitive (AR)

## Protein context {#protein}

Residue **207** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 96.66, 96% of residues very-high.

**7 experimental structure(s)** (PDB): [2AMY](https://www.rcsb.org/structure/2AMY), [2Q4R](https://www.rcsb.org/structure/2Q4R), [7O0C](https://www.rcsb.org/structure/7O0C), [7O1B](https://www.rcsb.org/structure/7O1B), [7O4G](https://www.rcsb.org/structure/7O4G), [7O58](https://www.rcsb.org/structure/7O58).

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

*Describes the biological roles of PMM2 (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:** PMM2's established molecular role includes phosphomannomutase activity. In Reactome, PMM2 is annotated in disease pathway(s) including **Defective PMM2 causes PMM2-CDG**.

**Disease mechanism (Reactome):** PMM2 loss or alteration is curated in [Defective PMM2 causes PMM2-CDG](https://reactome.org/content/detail/R-HSA-4043911).

### Pathways affected {#pathways}

PMM2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective PMM2 causes PMM2-CDG](https://reactome.org/content/detail/R-HSA-4043911) | curated |
| [Synthesis of GDP-mannose](https://reactome.org/content/detail/R-HSA-446205) | curated |

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

**Molecular function:** phosphomannomutase activity.

**Biological process:** obsolete GDP-mannose biosynthetic process from mannose, obsolete GDP-D-mannose biosynthetic process from fructose-6-phosphate.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-15.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-06-15 |

## Associated conditions {#conditions}

[PMM2-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/pmm2-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** PMM2-congenital disorder of glycosylation, PMM2-CDG, Congenital disorder of glycosylation, type Ia, CDG Ia, JAEKEN SYNDROME, PHOSPHOMANNOMUTASE 2 DEFICIENCY, CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE Ia.

## Same-residue context {#hotspot}

Residue **207** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PMM2 p.Phe207Ser](/variant/pmm2-p-phe207ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PMM2 variant pages (same residue, condition, or type): [PMM2 p.Phe207Ser](/variant/pmm2-p-phe207ser), [PMM2 c.178+1G>A](/variant/pmm2-c-178-plus-1g-a), [PMM2 c.178+2T>G](/variant/pmm2-c-178-plus-2t-g), [PMM2 c.179-1G>C](/variant/pmm2-c-179-minus-1g-c), [PMM2 c.179-25A>G](/variant/pmm2-c-179-minus-25a-g), [PMM2 c.255+1G>A](/variant/pmm2-c-255-plus-1g-a), [PMM2 c.255+2T>C](/variant/pmm2-c-255-plus-2t-c), [PMM2 c.256-1G>C](/variant/pmm2-c-256-minus-1g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2982366). 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.*