# NM_004577.4(PSPH):c.24G>T (p.Arg8Ser)

https://sugi.bio/variant/psph-p-arg8ser

## Summary

**PSPH p.Arg8Ser (c.24G>T)** is classified **Uncertain significance** in PSPH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-28). AlphaMissense: ambiguous (0.555); Very rare (popmax 0.00666%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1789352688 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00666%, afr)

## For patients & families {#patients}

This is a change in the PSPH 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 | [PSPH](https://sugi.bio/atlas/gene/PSPH/) |
| Protein change (HGVS p.) | p.Arg8Ser |
| Coding change (HGVS c.) | c.24G>T |
| MANE Select transcript | [NM_004577](https://www.ncbi.nlm.nih.gov/nuccore/NM_004577) |
| dbSNP | [rs1789352688](https://www.ncbi.nlm.nih.gov/snp/rs1789352688/) |
| Variant type | single nucleotide variant |
| Location | chr7:56021189-56021189 (GRCh38) |
| ClinVar | [VCV2375553](https://www.ncbi.nlm.nih.gov/clinvar/variation/2375553/) |

**All HGVS expressions:** `NC_000007.13:g.56088882C>A`, `NC_000007.14:g.56021189C>A`, `NG_011473.1:g.35387G>T`, `NM_001370503.1:c.24G>T`, `NM_001370504.1:c.24G>T`, `NM_001370505.1:c.24G>T`, `NM_001370506.1:c.24G>T`, `NM_001370507.1:c.24G>T`, `NM_001370508.1:c.24G>T`, `NM_001370509.1:c.24G>T`, `NM_001370510.1:c.24G>T`, `NM_001370511.1:c.24G>T`, `NM_001370512.1:c.24G>T`, `NM_001370513.1:c.24G>T`, `NM_001370514.1:c.24G>T`, `NM_001370515.1:c.24G>T`, `NM_001370516.1:c.24G>T`, `NM_001370517.1:c.24G>T`, `NM_001370518.1:c.24G>T`, `NM_001370519.1:c.24G>T`, `NM_001370520.1:c.24G>T`, `NM_001370521.1:c.24G>T`, `NM_001370522.1:c.24G>T`, `NM_004577.4:c.24G>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.555) — no call either way
- REVEL 0.391 (indeterminate)
- SaProt LLR -9.713 (tolerated)
- SpliceAI predicts **donor gain** (Δ 0.67) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.115, GERP 4.71, phastCons 0.982 — highly conserved
- 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 0.81** across the covering region of the MANE Select transcript (56,011,765–56,021,212), spanning 9,447 bp. Chi-square p 0.0022. 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 **0.67**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.67**.
- Population frequency (gnomAD v4.1): grpmax **0.00666%** (afr) · FAF95 0.00254% · FAF99 0.00161% · 5/75,086 in the highest group · 8/1,614,208 alleles overall — very rare (popmax 0.00666%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00666% | 15,017 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,253 |
| South Asian | 0.0011% | 91,086 |

*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}

**PSPH** population constraint: LOEUF 1.063, pLI 0.00012448, missense-Z 1.164; 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.*

Curated gene–disease validity (ClinGen):

- **neurometabolic disorder due to serine deficiency** — Moderate (AR)

## Protein context {#protein}

Residue **8** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 92.88, 81% of residues very-high.

**6 experimental structure(s)** (PDB): [1L8L](https://www.rcsb.org/structure/1L8L), [1L8O](https://www.rcsb.org/structure/1L8O), [1NNL](https://www.rcsb.org/structure/1NNL), [6HYJ](https://www.rcsb.org/structure/6HYJ), [6HYY](https://www.rcsb.org/structure/6HYY), [6Q6J](https://www.rcsb.org/structure/6Q6J).

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

*Describes the biological roles of PSPH (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:** PSPH's established molecular role includes magnesium ion binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Serine metabolism](https://reactome.org/content/detail/R-HSA-977347) | other |

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

**Molecular function:** magnesium ion binding, L-phosphoserine phosphatase activity, identical protein binding, protein homodimerization activity.

**Biological process:** L-serine metabolic process, L-serine biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-28.

**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 | 2022-01-28 |

## 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 PSPH variant pages (same residue, condition, or type): [PSPH p.Asn124Ser](/variant/psph-p-asn124ser), [PSPH p.Glu117Asp](/variant/psph-p-glu117asp), [PSPH p.Glu225Lys](/variant/psph-p-glu225lys), [PSPH p.Tyr212Cys](/variant/psph-p-tyr212cys), [PSPH p.Ala192Thr](/variant/psph-p-ala192thr), [PSPH p.Ala192Val](/variant/psph-p-ala192val), [PSPH p.Ala209Thr](/variant/psph-p-ala209thr), [PSPH p.Ala43Val](/variant/psph-p-ala43val).

### 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 2375553). 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.*