# NM_004077.3(CS):c.1121T>C (p.Phe374Ser)

https://sugi.bio/variant/cs-p-phe374ser

## Summary

**CS p.Phe374Ser (c.1121T>C)** is classified **Uncertain significance** in CS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: likely pathogenic (0.9775); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2547163881 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CS 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 | [CS](https://sugi.bio/atlas/gene/CS/) |
| Protein change (HGVS p.) | p.Phe374Ser |
| Coding change (HGVS c.) | c.1121T>C |
| MANE Select transcript | [NM_004077](https://www.ncbi.nlm.nih.gov/nuccore/NM_004077) |
| dbSNP | [rs2547163881](https://www.ncbi.nlm.nih.gov/snp/rs2547163881/) |
| Variant type | single nucleotide variant |
| Location | chr12:56273696-56273696 (GRCh38) |
| ClinVar | [VCV2607426](https://www.ncbi.nlm.nih.gov/clinvar/variation/2607426/) |

**All HGVS expressions:** `NC_000012.11:g.56667480A>G`, `NC_000012.12:g.56273696A>G`, `NM_004077.3:c.1121T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9775)
- REVEL 0.83 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.03 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.162, GERP 1.72, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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 0.44** across the covering region of the MANE Select transcript (56,273,087–56,285,946), spanning 12,859 bp. Chi-square p 7.5e-36. 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 (A>C, Δ0.52 donor 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CS** population constraint: LOEUF 0.356, pLI 0.99999, missense-Z 4.3605. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **374** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 94.56, 93% of residues very-high.

**11 experimental structure(s)** (PDB): [5UZP](https://www.rcsb.org/structure/5UZP), [5UZQ](https://www.rcsb.org/structure/5UZQ), [5UZR](https://www.rcsb.org/structure/5UZR), [8ZVL](https://www.rcsb.org/structure/8ZVL), [8ZVM](https://www.rcsb.org/structure/8ZVM), [8ZVR](https://www.rcsb.org/structure/8ZVR) — incl. mutant structure 5UZP.

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

*Describes the biological roles of CS (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:** CS's established molecular role includes RNA binding.


### Pathways affected {#pathways}

CS participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Citric acid cycle (TCA cycle)](https://reactome.org/content/detail/R-HSA-71403) | curated |
| [Maturation of TCA enzymes and regulation of TCA cycle](https://reactome.org/content/detail/R-HSA-9854311) | curated |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |
| [Mitochondrial protein import](https://reactome.org/content/detail/R-HSA-1268020) | electronic |

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

**Molecular function:** RNA binding, citrate synthase activity, identical protein binding.

**Biological process:** carbohydrate metabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-29.

**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 | 2023-06-29 |

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

## Similar variants {#similar}

Related CS variant pages (same residue, condition, or type): [CS p.Leu257=](/variant/cs-p-leu257), [CS p.Phe96=](/variant/cs-p-phe96), [CS p.Ala2Gly](/variant/cs-p-ala2gly), [CS p.Ala8Ser](/variant/cs-p-ala8ser), [CS p.Arg183Gly](/variant/cs-p-arg183gly), [CS p.Arg191Gln](/variant/cs-p-arg191gln), [CS p.Arg218Gln](/variant/cs-p-arg218gln), [CS p.Arg329Gln](/variant/cs-p-arg329gln).

### 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 2607426). 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.*