# NM_007293.3(C4A):c.2777C>T (p.Ala926Val)

https://sugi.bio/variant/c4a-p-ala926val

## Summary

**C4A p.Ala926Val (c.2777C>T)** is classified **Uncertain significance** in C4A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-06). AlphaMissense: likely benign (0.1334); Very rare (popmax 0.00224%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs762474221 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00224%, nfe)

## For patients & families {#patients}

This is a change in the C4A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [C4A](https://sugi.bio/atlas/gene/C4A/) |
| Protein change (HGVS p.) | p.Ala926Val |
| Coding change (HGVS c.) | c.2777C>T |
| MANE Select transcript | [NM_007293](https://www.ncbi.nlm.nih.gov/nuccore/NM_007293) |
| dbSNP | [rs762474221](https://www.ncbi.nlm.nih.gov/snp/rs762474221/) |
| Variant type | single nucleotide variant |
| Location | chr6:31994682-31994682 (GRCh38) |
| ClinVar | [VCV3136002](https://www.ncbi.nlm.nih.gov/clinvar/variation/3136002/) |

**All HGVS expressions:** `LRG_137:g.17626C>T`, `LRG_137t1:c.2777C>T`, `NC_000006.11:g.31962459C>T`, `NC_000006.12:g.31994682C>T`, `NG_011638.1:g.17626C>T`, `NM_001252204.2:c.2777C>T`, `NM_007293.3:c.2777C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1334)
- REVEL 0.068 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.6 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.623, GERP 0.725, phastCons 0.992 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 17.95**. 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 (C>G, Δ0.30 acceptor 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 **0.00224%** (nfe) · FAF95 0.00156% · FAF99 0.00133% · 26/1,159,398 in the highest group · 30/1,590,748 alleles overall — very rare (popmax 0.00224%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00324% | 30,861 |
| European (non-Finnish) (grpmax) | 0.00224% | 44,592 |
| Admixed American | 0.00167% | 59,814 |
| South Asian | 0.0011% | 91,048 |

Remaining individuals 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}

**C4A** population constraint: LOEUF 0.752, pLI 0.10773, missense-Z 3.795. *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 **926** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 83.56, 45% of residues very-high.

**12 experimental structure(s)** (PDB): [1HZF](https://www.rcsb.org/structure/1HZF), [5JPM](https://www.rcsb.org/structure/5JPM), [5JPN](https://www.rcsb.org/structure/5JPN), [5JTW](https://www.rcsb.org/structure/5JTW), [6YSQ](https://www.rcsb.org/structure/6YSQ), [7B2M](https://www.rcsb.org/structure/7B2M).

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

*Describes the biological roles of C4A (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:** C4A's established molecular role includes complement component C1q complex binding. In Reactome, C4A is annotated in disease pathway(s) including **Dengue virus activates/modulates innate and adaptive immune responses**.

**Disease mechanism (Reactome):** C4A loss or alteration is curated in [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588).

### Pathways affected {#pathways}

C4A participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588) | curated |
| [Activation of C3 and C5](https://reactome.org/content/detail/R-HSA-174577) | curated |
| [Initial triggering of complement](https://reactome.org/content/detail/R-HSA-166663) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |

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

**Molecular function:** complement component C1q complex binding.

**Biological process:** complement activation, complement activation, GZMK pathway, positive regulation of apoptotic cell clearance.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-06.

**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 | 2024-02-06 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related C4A variant pages (same residue, condition, or type): [C4A p.Ala926=](/variant/c4a-p-ala926), [C4A p.Ala1062Val](/variant/c4a-p-ala1062val), [C4A p.Ala1080Gly](/variant/c4a-p-ala1080gly), [C4A p.Ala1148Val](/variant/c4a-p-ala1148val), [C4A p.Ala1190Ser](/variant/c4a-p-ala1190ser), [C4A p.Ala1199Thr](/variant/c4a-p-ala1199thr), [C4A p.Ala1205Val](/variant/c4a-p-ala1205val), [C4A p.Ala1259Thr](/variant/c4a-p-ala1259thr).

### 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 3136002). 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.*