# NM_024596.5(MCPH1):c.477A>T (p.Ser159=)

https://sugi.bio/variant/mcph1-p-ser159

## Summary

**MCPH1 p.Ser159= (c.477A>T)** is classified **Conflicting classifications of pathogenicity** in MCPH1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-05-01). Rare (popmax 0.526%, nfe); Associated with microcephaly 1, primary, autosomal recessive.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs41313948 · 9 submitters · 1 linked condition · rare (popmax 0.526%, nfe)

## For patients & families {#patients}

This is a change in the MCPH1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 9 submitters, and is linked to microcephaly 1, primary, autosomal recessive.

*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/0015198/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MCPH1](https://sugi.bio/atlas/gene/MCPH1/) |
| Protein change (HGVS p.) | p.Ser159= |
| Coding change (HGVS c.) | c.477A>T |
| MANE Select transcript | [NM_024596](https://www.ncbi.nlm.nih.gov/nuccore/NM_024596) |
| dbSNP | [rs41313948](https://www.ncbi.nlm.nih.gov/snp/rs41313948/) |
| Variant type | single nucleotide variant |
| Location | chr8:6438993-6438993 (GRCh38) |
| ClinVar | [VCV158870](https://www.ncbi.nlm.nih.gov/clinvar/variation/158870/) |

**All HGVS expressions:** `NC_000008.10:g.6296514A>T`, `NC_000008.11:g.6438993A>T`, `NG_016619.2:g.37402A>T`, `NM_001172574.2:c.477A>T`, `NM_001172575.2:c.436+2831A>T`, `NM_001322042.1:c.477A>T`, `NM_001322042.2:c.477A>T`, `NM_001322043.2:c.471A>T`, `NM_001322045.2:c.375A>T`, `NM_001363979.1:c.477A>T`, `NM_001363980.2:c.477A>T`, `NM_024596.5:c.477A>T`, `NR_136159.2:n.403A>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 -9.914, GERP -3.64 — fast-evolving / accelerated position
- CADD: **PHRED 0.23**. 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 **0.526%** (nfe) · FAF95 0.515% · FAF99 0.51% · 6,191/1,177,504 in the highest group · 6,893/1,611,144 alleles overall — rare (popmax 0.526%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.526% | 190 |
| Remaining individuals (not grpmax-eligible) | 0.407% | 246 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.297% | 336 |
| Finnish (not grpmax-eligible) | 0.232% | 431 |
| Admixed American | 0.205% | 488 |
| Middle Eastern | 0.0991% | 1,009 |
| African / African-American | 0.084% | 1,190 |
| South Asian | 0.022% | 4,552 |

*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}

**MCPH1** population constraint: LOEUF 1.342, pLI 1.8376e-32, missense-Z -4.7142. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **microcephaly with intellectual disability** — Definitive (AR)
- **familial ovarian cancer** — No Known Disease Relationship (AD)
- **hereditary breast carcinoma** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 59.80, 29% of residues very-high.

**9 experimental structure(s)** (PDB): [2WT8](https://www.rcsb.org/structure/2WT8), [3KTF](https://www.rcsb.org/structure/3KTF), [3PA6](https://www.rcsb.org/structure/3PA6), [3SHT](https://www.rcsb.org/structure/3SHT), [3SHV](https://www.rcsb.org/structure/3SHV), [3SZM](https://www.rcsb.org/structure/3SZM).

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

*Describes the biological roles of MCPH1 (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:** MCPH1's established molecular role includes identical protein binding.


### Pathways affected {#pathways}

MCPH1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Condensation of Prophase Chromosomes](https://reactome.org/content/detail/R-HSA-2299718) | curated |

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

**Molecular function:** identical protein binding.

**Biological process:** negative regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-05-01.

**Submitter consensus:** conflicting (4 Likely benign, 2 Uncertain significance, 2 Benign, 1 benign).

**Submission history:** 9 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2013-02-15 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-05-04 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-04-01 |
| Athena Diagnostics | benign | criteria provided, single submitter | clinical testing | 2024-09-23 |
| Eurofins Ntd Llc (ga) | Likely benign | criteria provided, single submitter | clinical testing | 2015-04-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-05-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

## Associated conditions {#conditions}

[microcephaly 1, primary, autosomal recessive](https://sugi.bio/atlas/disease/microcephaly-1-primary-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Microcephaly 1, primary, autosomal recessive, not specified, not provided, MCPH1-related disorder, MCPH1-related condition, AllHighlyPenetrant, none provided, PREMATURE CHROMOSOME CONDENSATION SYNDROME, PCC SYNDROME, PREMATURE CHROMOSOME CONDENSATION WITH MICROCEPHALY AND MENTAL RETARDATION.

## Same-residue context {#hotspot}

Residue **159** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MCPH1 p.Ser159_Leu160insTer](/variant/mcph1-p-ser159-leu160inster). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MCPH1 variant pages (same residue, condition, or type): [MCPH1 p.Ser159_Leu160insTer](/variant/mcph1-p-ser159-leu160inster), [MCPH1 c.321+2T>C](/variant/mcph1-c-321-plus-2t-c), [MCPH1 c.322-1G>C](/variant/mcph1-c-322-minus-1g-c), [MCPH1 p.Gln386Ter](/variant/mcph1-p-gln386ter), [MCPH1 p.Gly245Ter](/variant/mcph1-p-gly245ter), [MCPH1 p.Leu542Ter](/variant/mcph1-p-leu542ter), [MCPH1 p.Ser72Leu](/variant/mcph1-p-ser72leu), [MCPH1 c.1935+6T>C](/variant/mcph1-c-1935-plus-6t-c).

### 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 158870). 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.*