# NM_014489.4(PGAP2):c.606C>T (p.Ile202=)

https://sugi.bio/variant/pgap2-p-ile202

## Summary

**PGAP2 p.Ile202= (c.606C>T)** is classified **Likely benign** in PGAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). Ultra-rare (popmax 0.0164%, mid).

**At a glance:** Likely benign · review: Single submitter · rsID rs780919622 · 1 submitter · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the PGAP2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [PGAP2](https://sugi.bio/atlas/gene/PGAP2/) |
| Protein change (HGVS p.) | p.Ile202= |
| Coding change (HGVS c.) | c.606C>T |
| MANE Select transcript | [NM_014489](https://www.ncbi.nlm.nih.gov/nuccore/NM_014489) |
| dbSNP | [rs780919622](https://www.ncbi.nlm.nih.gov/snp/rs780919622/) |
| Variant type | single nucleotide variant |
| Location | chr11:3824274-3824274 (GRCh38) |
| ClinVar | [VCV724055](https://www.ncbi.nlm.nih.gov/clinvar/variation/724055/) |

**All HGVS expressions:** `NC_000011.10:g.3824274C>T`, `NC_000011.9:g.3845504C>T`, `NG_051812.1:g.31551C>T`, `NM_001145438.3:c.423C>T`, `NM_001256235.2:c.477C>T`, `NM_001256236.2:c.606C>T`, `NM_001256237.2:c.423C>T`, `NM_001256238.2:c.423C>T`, `NM_001256239.2:c.423C>T`, `NM_001256240.2:c.423C>T`, `NM_001283038.2:c.423C>T`, `NM_001283039.2:c.346C>T`, `NM_001283040.1:c.166C>T`, `NM_001346397.2:c.576C>T`, `NM_001346398.2:c.423C>T`, `NM_001346399.2:c.433C>T`, `NM_001346400.2:c.423C>T`, `NM_001346401.2:c.433C>T`, `NM_001346402.2:c.543C>T`, `NM_001346403.1:c.606C>T`, `NM_001346404.1:c.423C>T`, `NM_001346405.1:c.423C>T`, `NM_014489.4:c.606C>T`, `NR_027016.3:n.350C>T`, `NR_027017.4:n.743C>T`, `NR_027018.2:n.571C>T`, `NR_045923.2:n.365C>T`, `NR_045925.2:n.287C>T`, `NR_045926.2:n.287C>T`, `NR_045927.2:n.365C>T`, `NR_045929.2:n.478C>T`, `NR_104270.2:n.365C>T`, `NR_104271.2:n.625C>T`, `NR_104272.2:n.350C>T`, `NR_144427.2:n.365C>T`, `NR_144428.2:n.610C>T`, `NR_144429.2:n.350C>T`, `NR_144430.2:n.97C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.804, GERP -2.99, phastCons 1 — weakly conserved position
- CADD: **PHRED 1.732**. 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 deltas (raw): acceptor loss **0.22**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 4 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0164%** (mid) · FAF95 0.00215% · FAF99 0.00191% · 1/6,084 in the highest group · 41/1,614,088 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,084 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,828 |
| European (non-Finnish) | 0.00297% | 33,715 |
| African / African-American | 0.00133% | 74,934 |
| South Asian | 0.0011% | 91,090 |

*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}

**PGAP2** population constraint: LOEUF 0.871, pLI 0.00010679, missense-Z 1.6257. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.00, 73% of residues very-high.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-19.

**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 | 2024-08-19 |

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

## Similar variants {#similar}

Related PGAP2 variant pages (same residue, condition, or type): [PGAP2 p.Ala127Val](/variant/pgap2-p-ala127val), [PGAP2 p.Arg238Pro](/variant/pgap2-p-arg238pro), [PGAP2 p.Thr294Met](/variant/pgap2-p-thr294met), [PGAP2 c.602-3C>T](/variant/pgap2-c-602-minus-3c-t), [PGAP2 p.Ala187Thr](/variant/pgap2-p-ala187thr), [PGAP2 p.Ala33Thr](/variant/pgap2-p-ala33thr), [PGAP2 p.Arg238Cys](/variant/pgap2-p-arg238cys), [PGAP2 p.Asn205Lys](/variant/pgap2-p-asn205lys).

### 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 724055). 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.*