# NM_025149.6(ACSF2):c.1124C>T (p.Ser375Leu)

https://sugi.bio/variant/acsf2-p-ser375leu

## Summary

**ACSF2 p.Ser375Leu (c.1124C>T)** is classified **Uncertain significance** in ACSF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-10). AlphaMissense: likely benign (0.1776); Very rare (popmax 0.00288%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs768330040 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00288%, nfe)

## For patients & families {#patients}

This is a change in the ACSF2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [ACSF2](https://sugi.bio/atlas/gene/ACSF2/) |
| Protein change (HGVS p.) | p.Ser375Leu |
| Coding change (HGVS c.) | c.1124C>T |
| MANE Select transcript | [NM_025149](https://www.ncbi.nlm.nih.gov/nuccore/NM_025149) |
| dbSNP | [rs768330040](https://www.ncbi.nlm.nih.gov/snp/rs768330040/) |
| Variant type | single nucleotide variant |
| Location | chr17:50463895-50463895 (GRCh38) |
| ClinVar | [VCV2274404](https://www.ncbi.nlm.nih.gov/clinvar/variation/2274404/) |

**All HGVS expressions:** `NC_000017.10:g.48541256C>T`, `NC_000017.11:g.50463895C>T`, `NM_001288968.2:c.1199C>T`, `NM_001288969.2:c.1085C>T`, `NM_001288970.2:c.995C>T`, `NM_001288971.2:c.644C>T`, `NM_001288972.2:c.644C>T`, `NM_025149.6:c.1124C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1776)
- REVEL 0.445 (indeterminate)
- SaProt LLR -13.8 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 7.642, GERP 1.36, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.5**. 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 0.82** across the covering region of the MANE Select transcript (50,426,262–50,474,549), spanning 48,287 bp. Chi-square p 5.1e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.36 donor loss), 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 **0.00288%** (nfe) · FAF95 0.00207% · FAF99 0.00183% · 34/1,180,028 in the highest group · 36/1,613,984 alleles overall — very rare (popmax 0.00288%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00288% | 34,707 |
| Admixed American | 0.00167% | 60,002 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |

*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}

**ACSF2** population constraint: LOEUF 0.844, pLI 6.4482e-12, missense-Z 1.8965. *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 89.40, 79% of residues very-high.

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

*Describes the biological roles of ACSF2 (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:** ACSF2's established molecular role includes medium-chain fatty acid-CoA ligase activity.


### Pathways affected {#pathways}

ACSF2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial Fatty Acid Beta-Oxidation](https://reactome.org/content/detail/R-HSA-77289) | curated |

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

**Molecular function:** medium-chain fatty acid-CoA ligase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-11-10.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-10 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ACSF2 variant pages (same residue, condition, or type): [CHAD p.Leu226=](/variant/chad-p-leu226), [CHAD p.Pro349=](/variant/chad-p-pro349), [CHAD p.Thr350Ile](/variant/chad-p-thr350ile), [ACSF2 p.Ala112Ser](/variant/acsf2-p-ala112ser), [ACSF2 p.Ala15Pro](/variant/acsf2-p-ala15pro), [ACSF2 p.Ala15Thr](/variant/acsf2-p-ala15thr), [ACSF2 p.Ala160Pro](/variant/acsf2-p-ala160pro), [ACSF2 p.Ala160Val](/variant/acsf2-p-ala160val).

### 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 2274404). 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.*