# NM_032861.4(SERAC1):c.917G>A (p.Arg306Gln)

https://sugi.bio/variant/serac1-p-arg306gln

## Summary

**SERAC1 p.Arg306Gln (c.917G>A)** is classified **Benign/Likely benign** in SERAC1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.0602); Rare (popmax 0.744%, afr); Associated with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs114943513 · 6 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.744%, afr)

## For patients & families {#patients}

This is a change in the SERAC1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 6 submitters, and is linked to 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome.

*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 |
| Diagnostic panels | SERAC1 is a diagnostic-grade gene on 17 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012963/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SERAC1](https://sugi.bio/atlas/gene/SERAC1/) |
| Protein change (HGVS p.) | p.Arg306Gln |
| Coding change (HGVS c.) | c.917G>A |
| MANE Select transcript | [NM_032861](https://www.ncbi.nlm.nih.gov/nuccore/NM_032861) |
| dbSNP | [rs114943513](https://www.ncbi.nlm.nih.gov/snp/rs114943513/) |
| Variant type | single nucleotide variant |
| Location | chr6:158128206-158128206 (GRCh38) |
| ClinVar | [VCV379604](https://www.ncbi.nlm.nih.gov/clinvar/variation/379604/) |

**All HGVS expressions:** `NC_000006.11:g.158549238C>T`, `NC_000006.12:g.158128206C>T`, `NG_032889.1:g.45075G>A`, `NM_032861.4:c.917G>A`, `NR_073096.2:n.927G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0602)
- REVEL 0.13 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.358 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.107, GERP -2.18, phastCons 0.014 — weakly conserved position
- CADD: **PHRED 0.335**. 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 0.79** across the covering region of the MANE Select transcript (158,111,369–158,158,363), spanning 46,994 bp. Chi-square p 3.1e-09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.744%** (afr) · FAF95 0.693% · FAF99 0.673% · 558/75,016 in the highest group · 717/1,614,118 alleles overall — rare (popmax 0.744%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.744% | 134 |
| Admixed American | 0.138% | 723 |
| Remaining individuals (not grpmax-eligible) | 0.0512% | 1,953 |
| Middle Eastern | 0.0495% | 2,021 |
| South Asian | 0.0209% | 4,794 |
| East Asian | 0.0134% | 7,480 |
| European (non-Finnish) | 0.00136% | 73,750 |

*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}

**SERAC1** population constraint: LOEUF 0.681, pLI 0.00021364, missense-Z 2.3086. *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):

- **Leigh syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 78.66, 52% of residues very-high.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-19.

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

**Submission history:** 6 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-09-21 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-19 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-07 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2022-03-15 |

## Associated conditions {#conditions}

[3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome](https://sugi.bio/atlas/disease/3-methylglutaconic-aciduria-with-deafness-encephalopathy-and-leigh-like-syndrome/).

**Reported phenotype names (ClinVar):** 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, not specified, not provided, none provided, AllHighlyPenetrant, 3-METHYLGLUTACONIC ACIDURIA, TYPE VI, SERAC1 Deficiency, MEGDEL syndrome.

## Similar variants {#similar}

Related SERAC1 variant pages (same residue, condition, or type): [SERAC1 p.Arg306Ter](/variant/serac1-p-arg306ter), [SERAC1 c.1403+1G>C](/variant/serac1-c-1403-plus-1g-c), [SERAC1 p.Arg148Ter](/variant/serac1-p-arg148ter), [SERAC1 p.Arg368Ter](/variant/serac1-p-arg368ter), [SERAC1 p.Arg387Ter](/variant/serac1-p-arg387ter), [SERAC1 p.Arg447Ter](/variant/serac1-p-arg447ter), [SERAC1 p.Arg68Ter](/variant/serac1-p-arg68ter), [SERAC1 p.Gln376Ter](/variant/serac1-p-gln376ter).

### 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 379604). 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.*