# NM_014423.4(AFF4):c.2303A>G (p.His768Arg)

https://sugi.bio/variant/aff4-p-his768arg

## Summary

**AFF4 p.His768Arg (c.2303A>G)** is classified **Uncertain significance** in AFF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-11). AlphaMissense: ambiguous (0.4113); Very rare (popmax 0.00234%, sas); Associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs144628972 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00234%, sas)

## For patients & families {#patients}

This is a change in the AFF4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012845/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AFF4](https://sugi.bio/atlas/gene/AFF4/) |
| Protein change (HGVS p.) | p.His768Arg |
| Coding change (HGVS c.) | c.2303A>G |
| MANE Select transcript | [NM_014423](https://www.ncbi.nlm.nih.gov/nuccore/NM_014423) |
| dbSNP | [rs144628972](https://www.ncbi.nlm.nih.gov/snp/rs144628972/) |
| Variant type | single nucleotide variant |
| Location | chr5:132896327-132896327 (GRCh38) |
| ClinVar | [VCV1487936](https://www.ncbi.nlm.nih.gov/clinvar/variation/1487936/) |

**All HGVS expressions:** `NC_000005.10:g.132896327T>C`, `NC_000005.9:g.132232019T>C`, `NG_030340.1:g.72336A>G`, `NM_014423.4:c.2303A>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4113) — no call either way
- REVEL 0.252 (benign-leaning)
- SaProt LLR -6.062 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- SpliceAI predicts **donor gain** (Δ 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.923, GERP 5.17, phastCons 1 — highly conserved
- CADD: **PHRED 27.0**. 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 1.05** across the covering region of the MANE Select transcript (132,889,080–132,896,615), spanning 7,535 bp. Chi-square p 0.44. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.25**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.25**.
- Population frequency (gnomAD v4.1): grpmax **0.00234%** (sas) · FAF95 0.000388% · FAF99 0.000145% · 2/85,638 in the highest group · 6/1,586,386 alleles overall — very rare (popmax 0.00234%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00234% | 42,819 |
| European (non-Finnish) | 0.000341% | 292,990 |

*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}

**AFF4** population constraint: LOEUF 0.114, pLI 1, missense-Z 3.6501. *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 **768** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 54.62, 18% of residues very-high.

**9 experimental structure(s)** (PDB): [4IMY](https://www.rcsb.org/structure/4IMY), [4OGR](https://www.rcsb.org/structure/4OGR), [4OR5](https://www.rcsb.org/structure/4OR5), [5JW9](https://www.rcsb.org/structure/5JW9), [5L1Z](https://www.rcsb.org/structure/5L1Z), [6CYT](https://www.rcsb.org/structure/6CYT).

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

*Describes the biological roles of AFF4 (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}

AFF4 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of RNA Pol II elongation complex ](https://reactome.org/content/detail/R-HSA-112382) | curated |
| [RNA Polymerase II Pre-transcription Events](https://reactome.org/content/detail/R-HSA-674695) | curated |
| [RNA Polymerase II Transcription Elongation](https://reactome.org/content/detail/R-HSA-75955) | curated |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-11 |

## Associated conditions {#conditions}

[cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome](https://sugi.bio/atlas/disease/cognitive-impairment-coarse-facies-heart-defects-obesity-pulmonary-involvement-short-stature-skeletal-dysplasia-syndrome/).

**Reported phenotype names (ClinVar):** Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome, COGNITIVE IMPAIRMENT, COARSE FACIES, HEART DEFECTS, OBESITY, PULMONARY INVOLVEMENT, SHORT STATURE, AND SKELETAL DYSPLASIA, Chops syndrome, AFF4-Related CHOPS Syndrome.

## Similar variants {#similar}

Related AFF4 variant pages (same residue, condition, or type): [AFF4 p.Arg258Trp](/variant/aff4-p-arg258trp), [AFF4 p.Met260Val](/variant/aff4-p-met260val), [AFF4 p.Pro253Leu](/variant/aff4-p-pro253leu), [AFF4 p.Thr254Ser](/variant/aff4-p-thr254ser), [AFF4 c.1133+3A>G](/variant/aff4-c-1133-plus-3a-g), [AFF4 p.Ala114Thr](/variant/aff4-p-ala114thr), [AFF4 p.Ala114Val](/variant/aff4-p-ala114val), [AFF4 p.Ala27Thr](/variant/aff4-p-ala27thr).

### 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 1487936). 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.*