# NM_020639.3(RIPK4):c.1311C>T (p.Ser437=)

https://sugi.bio/variant/ripk4-p-ser437

## Summary

**RIPK4 p.Ser437= (c.1311C>T)** is classified **Benign/Likely benign** in RIPK4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-03-23). Low-frequency (popmax 3.44%, afr); Associated with Bartsocas-Papas syndrome 1.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs56149248 · 4 submitters · 1 linked condition · low-frequency (popmax 3.44%, afr)

## For patients & families {#patients}

This is a change in the RIPK4 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters, and is linked to Bartsocas-Papas syndrome 1.

*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/0004436/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RIPK4](https://sugi.bio/atlas/gene/RIPK4/) |
| Protein change (HGVS p.) | p.Ser437= |
| Coding change (HGVS c.) | c.1311C>T |
| MANE Select transcript | [NM_020639](https://www.ncbi.nlm.nih.gov/nuccore/NM_020639) |
| dbSNP | [rs56149248](https://www.ncbi.nlm.nih.gov/snp/rs56149248/) |
| Variant type | single nucleotide variant |
| Location | chr21:41741882-41741882 (GRCh38) |
| ClinVar | [VCV340021](https://www.ncbi.nlm.nih.gov/clinvar/variation/340021/) |

**All HGVS expressions:** `NC_000021.8:g.43162042G>A`, `NC_000021.9:g.41741882G>A`, `NG_032113.2:g.30208C>T`, `NM_020639.3:c.1311C>T`

## 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 -0.134, GERP -2.43 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.927**. 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 **3.44%** (afr) · FAF95 3.33% · FAF99 3.29% · 2,582/75,032 in the highest group · 3,220/1,613,402 alleles overall — low-frequency (popmax 3.44%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 3.44% | 29 |
| Admixed American | 0.346% | 289 |
| Remaining individuals (not grpmax-eligible) | 0.29% | 345 |
| Middle Eastern | 0.198% | 505 |
| South Asian | 0.0505% | 1,980 |
| European (non-Finnish) | 0.016% | 6,243 |
| East Asian | 0.00446% | 22,436 |

*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}

**RIPK4** population constraint: LOEUF 0.577, pLI 0.62495, missense-Z 2.2992; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 75.41, 48% of residues very-high.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-03-23.

**Submitter consensus:** conflicting (2 Benign, 2 Likely benign).

**Submission history:** 4 submissions (2018–2021); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-03-23 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[Bartsocas-Papas syndrome 1](https://sugi.bio/atlas/disease/bartsocas-papas-syndrome-1/).

**Reported phenotype names (ClinVar):** Bartsocas-Papas syndrome 1, not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided, Bartsocas-Papas syndrome, MULTIPLE PTERYGIUM SYNDROME, ASLAN TYPE, PTERYGIUM, POPLITEAL, LETHAL TYPE.

## Similar variants {#similar}

Related RIPK4 variant pages (same residue, condition, or type): [RIPK4 c.*1361T>A](/variant/ripk4-c-star-1361t-a), [RIPK4 p.Ala126Val](/variant/ripk4-p-ala126val), [RIPK4 p.Arg241Cys](/variant/ripk4-p-arg241cys), [RIPK4 p.Arg260His](/variant/ripk4-p-arg260his), [RIPK4 p.Arg271Gln](/variant/ripk4-p-arg271gln), [RIPK4 p.Arg320Gln](/variant/ripk4-p-arg320gln), [RIPK4 p.Arg493Trp](/variant/ripk4-p-arg493trp), [RIPK4 p.Arg521Trp](/variant/ripk4-p-arg521trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 340021). 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.*