# NM_030799.9(YIPF5):c.542C>T (p.Ala181Val)

https://sugi.bio/variant/yipf5-p-ala181val

## Summary

**YIPF5 p.Ala181Val (c.542C>T)** is classified **Pathogenic** in YIPF5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-04-16). AlphaMissense: likely pathogenic (0.6595); Absent from gnomAD v4.1; Associated with microcephaly, epilepsy, and diabetes syndrome 2.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs1752071425 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the YIPF5 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to microcephaly, epilepsy, and diabetes syndrome 2.

*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/0018439/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [YIPF5](https://sugi.bio/atlas/gene/YIPF5/) |
| Protein change (HGVS p.) | p.Ala181Val |
| Coding change (HGVS c.) | c.542C>T |
| MANE Select transcript | [NM_030799](https://www.ncbi.nlm.nih.gov/nuccore/NM_030799) |
| dbSNP | [rs1752071425](https://www.ncbi.nlm.nih.gov/snp/rs1752071425/) |
| Variant type | single nucleotide variant |
| Location | chr5:144162287-144162287 (GRCh38) |
| ClinVar | [VCV1064542](https://www.ncbi.nlm.nih.gov/clinvar/variation/1064542/) |

**All HGVS expressions:** `NC_000005.10:g.144162287G>A`, `NC_000005.9:g.143541851G>A`, `NM_001024947.4:c.542C>T`, `NM_001271732.2:c.380C>T`, `NM_030799.9:c.542C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.6595) — concordant with the pathogenic call
- REVEL 0.164 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -7.658 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- SpliceAI predicts **donor gain** (Δ 0.64) — consistent with the pathogenic call
- Conservation: phyloP 11.892, GERP 2.84, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 31.0**. 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 0.93** across the covering region of the MANE Select transcript (144,160,400–144,169,955), spanning 9,555 bp. Chi-square p 0.25. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.64**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.64**.
- Pangolin: Δ**0.42** (gain), gain 0.42 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is 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}

**YIPF5** population constraint: LOEUF 0.464, pLI 0.99332, missense-Z 0.72561. *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 **181** lies in a UniProt-annotated variant site (in meds2; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 66.45, 19% of residues very-high.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2021-04-16.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2021-04-16 |

## Associated conditions {#conditions}

[microcephaly, epilepsy, and diabetes syndrome 2](https://sugi.bio/atlas/disease/microcephaly-epilepsy-and-diabetes-syndrome-2/).

**Reported phenotype names (ClinVar):** Microcephaly, epilepsy, and diabetes syndrome 2.

## Similar variants {#similar}

Related YIPF5 variant pages (same residue, condition, or type): [YIPF5 p.Val175Asp](/variant/yipf5-p-val175asp), [YIPF5 p.Trp218Arg](/variant/yipf5-p-trp218arg), [YIPF5 p.Val51Ile](/variant/yipf5-p-val51ile), [YIPF5 p.Ala198Thr](/variant/yipf5-p-ala198thr), [YIPF5 p.Ala245Thr](/variant/yipf5-p-ala245thr), [YIPF5 p.Asp20Gly](/variant/yipf5-p-asp20gly), [YIPF5 p.Asp43Asn](/variant/yipf5-p-asp43asn), [YIPF5 p.Asp43Val](/variant/yipf5-p-asp43val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1064542). 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.*