# NM_003172.4(SURF1):c.276A>C (p.Ala92=)

https://sugi.bio/variant/surf1-p-ala92

## Summary

**SURF1 p.Ala92= (c.276A>C)** is classified **Likely benign** in SURF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-20). Very rare (popmax 0.000254%, nfe); Associated with Leigh syndrome.

**At a glance:** Likely benign · review: Single submitter · rsID rs2490622624 · 1 submitter · 1 linked condition · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the SURF1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Leigh 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, Mitochondrial inheritance, X-linked recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 14 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SURF1 is a diagnostic-grade gene on 17 Genomics England panels |

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

- Increased circulating lactate concentration — Very frequent (99-80%)
- Increased CSF lactate — Very frequent (99-80%)
- Lactic acidosis — Very frequent (99-80%)
- Lacticaciduria — Very frequent (99-80%)
- Floppy infant — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Abnormality of movement — Very frequent (99-80%)
- Sensorineural hearing impairment — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006877/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SURF1](https://sugi.bio/atlas/gene/SURF1/) |
| Protein change (HGVS p.) | p.Ala92= |
| Coding change (HGVS c.) | c.276A>C |
| MANE Select transcript | [NM_003172](https://www.ncbi.nlm.nih.gov/nuccore/NM_003172) |
| dbSNP | [rs2490622624](https://www.ncbi.nlm.nih.gov/snp/rs2490622624/) |
| Variant type | single nucleotide variant |
| Location | chr9:133354706-133354706 (GRCh38) |
| ClinVar | [VCV2729085](https://www.ncbi.nlm.nih.gov/clinvar/variation/2729085/) |

**All HGVS expressions:** `NC_000009.11:g.136221561T>G`, `NC_000009.12:g.133354706T>G`, `NG_008477.1:g.6801A>C`, `NG_008477.2:g.6781A>C`, `NM_001280787.1:c.-52A>C`, `NM_003172.4:c.276A>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 -3.008, GERP -4.08 — fast-evolving / accelerated position
- CADD: **PHRED 5.395**. 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: **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 **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,180,016 in the highest group · 3/1,613,538 alleles overall — very rare (popmax 0.000254%, nfe).

*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}

**SURF1** population constraint: LOEUF 1.559, pLI 4.5412e-18, missense-Z -1.3117; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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):

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

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.62, 65% of residues very-high.

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

*Describes the biological roles of SURF1 (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.*


### Pathways affected {#pathways}

SURF1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Complex IV assembly](https://reactome.org/content/detail/R-HSA-9864848) | curated |

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

**Biological process:** mitochondrial respiratory chain complex IV assembly.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-20.

**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 | 2023-03-20 |

## Associated conditions {#conditions}

[Leigh syndrome](https://sugi.bio/atlas/disease/leigh-syndrome/).

**Reported phenotype names (ClinVar):** Leigh syndrome, LEIGH SYNDROME, NUCLEAR, Leigh Disease, Leigh's syndrome, Subacute necrotizing encephalopathy, Necrotizing encephalopathy infantile subacute of Leigh, Leigh's necrotizing encephalopathy, Leigh's disease, Leigh Syndrome (mtDNA deletion).

## Similar variants {#similar}

Related SURF1 variant pages (same residue, condition, or type): [SURF1 c.106+1G>C](/variant/surf1-c-106-plus-1g-c), [SURF1 c.240+1G>T](/variant/surf1-c-240-plus-1g-t), [SURF1 c.324-11T>G](/variant/surf1-c-324-minus-11t-g), [SURF1 c.516-2A>G](/variant/surf1-c-516-minus-2a-g), [SURF1 c.588+1G>C](/variant/surf1-c-588-plus-1g-c), [SURF1 c.751+1G>A](/variant/surf1-c-751-plus-1g-a), [SURF1 c.752-1G>C](/variant/surf1-c-752-minus-1g-c), [SURF1 c.752-3C>G](/variant/surf1-c-752-minus-3c-g).

### 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 2729085). 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.*