# NM_001278689.2(EOGT):c.783C>T (p.His261=)

https://sugi.bio/variant/eogt-p-his261

## Summary

**EOGT p.His261= (c.783C>T)** is classified **Benign/Likely benign** in EOGT (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-19). Low-frequency (popmax 1.38%, sas); Associated with Adams-Oliver syndrome 4.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs147327086 · 5 submitters · 1 linked condition · low-frequency (popmax 1.38%, sas)

## For patients & families {#patients}

This is a change in the EOGT gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to Adams-Oliver syndrome 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015941/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EOGT](https://sugi.bio/atlas/gene/EOGT/) |
| Protein change (HGVS p.) | p.His261= |
| Coding change (HGVS c.) | c.783C>T |
| MANE Select transcript | [NM_001278689](https://www.ncbi.nlm.nih.gov/nuccore/NM_001278689) |
| dbSNP | [rs147327086](https://www.ncbi.nlm.nih.gov/snp/rs147327086/) |
| Variant type | single nucleotide variant |
| Location | chr3:68998059-68998059 (GRCh38) |
| ClinVar | [VCV376918](https://www.ncbi.nlm.nih.gov/clinvar/variation/376918/) |

**All HGVS expressions:** `NC_000003.11:g.69047210G>A`, `NC_000003.12:g.68998059G>A`, `NG_042829.1:g.20836C>T`, `NM_001278689.2:c.783C>T`, `NM_173654.3:c.783C>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 (below), not from a missing predictor score.
- Conservation: phyloP -4.073, GERP -4.15 — fast-evolving / accelerated position
- CADD: **PHRED 1.947**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.40 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **1.38%** (sas) · FAF95 1.32% · FAF99 1.29% · 1,225/88,704 in the highest group · 8,560/1,601,624 alleles overall — low-frequency (popmax 1.38%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 1.75% | 57 |
| South Asian (grpmax) | 1.38% | 72 |
| Middle Eastern | 0.744% | 134 |
| European (non-Finnish) | 0.565% | 177 |
| Remaining individuals (not grpmax-eligible) | 0.404% | 247 |
| Admixed American | 0.29% | 345 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.153% | 654 |
| Finnish (not grpmax-eligible) | 0.15% | 666 |
| African / African-American | 0.0885% | 1,130 |
| East Asian | 0.0382% | 2,615 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**EOGT** population constraint: LOEUF 1.121, pLI 4.8218e-07, missense-Z -0.4678. *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):

- **Adams-Oliver syndrome 4** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.71, 83% of residues very-high.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-19.

**Submitter consensus:** conflicting (3 Benign, 2 Likely benign).

**Submission history:** 5 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-06-11 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Likely benign | criteria provided, single submitter | clinical testing | 2016-07-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-19 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2025-12-01 |

## Associated conditions {#conditions}

[Adams-Oliver syndrome 4](https://sugi.bio/atlas/disease/adams-oliver-syndrome-4/).

**Reported phenotype names (ClinVar):** Adams-Oliver syndrome 4, not provided, none provided.

## Similar variants {#similar}

Related EOGT variant pages (same residue, condition, or type): [EOGT c.1335-1G>A](/variant/eogt-c-1335-minus-1g-a), [EOGT c.311+1G>T](/variant/eogt-c-311-plus-1g-t), [EOGT c.621-2A>T](/variant/eogt-c-621-minus-2a-t), [EOGT p.Arg372Trp](/variant/eogt-p-arg372trp), [EOGT p.Arg377Trp](/variant/eogt-p-arg377trp), [EOGT p.Arg452His](/variant/eogt-p-arg452his), [EOGT p.Arg470Trp](/variant/eogt-p-arg470trp), [EOGT p.Asp252Asn](/variant/eogt-p-asp252asn).

### 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 376918). 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.*