# NM_004628.5(XPC):c.736C>T (p.Pro246Ser)

https://sugi.bio/variant/xpc-p-pro246ser

## Summary

**XPC p.Pro246Ser (c.736C>T)** is classified **Uncertain significance** in XPC (ClinVar, No assertion criteria, 2 submitters; last evaluated 2017-11-02). AlphaMissense: likely benign (0.1255); Ultra-rare (popmax 0.0134%, afr); Associated with xeroderma pigmentosum group C.

**At a glance:** Uncertain significance · review: No assertion criteria · rsID rs587778761 · 2 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0134%, afr)

## For patients & families {#patients}

This is a change in the XPC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to xeroderma pigmentosum group C.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (United States) |
| Diagnostic panels | XPC is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Xeroderma pigmentosum** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypogonadism — Very frequent (99-80%)
- Abnormality of the dentition — Very frequent (99-80%)
- Conjunctival telangiectasia — Very frequent (99-80%)
- Optic atrophy — Very frequent (99-80%)
- Dry skin — Very frequent (99-80%)
- Thin skin — Very frequent (99-80%)
- Cutaneous photosensitivity — Very frequent (99-80%)
- Telangiectasia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005626/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [XPC](https://sugi.bio/atlas/gene/XPC/) |
| Protein change (HGVS p.) | p.Pro246Ser |
| Coding change (HGVS c.) | c.736C>T |
| MANE Select transcript | [NM_004628](https://www.ncbi.nlm.nih.gov/nuccore/NM_004628) |
| dbSNP | [rs587778761](https://www.ncbi.nlm.nih.gov/snp/rs587778761/) |
| Variant type | single nucleotide variant |
| Location | chr3:14165471-14165471 (GRCh38) |
| ClinVar | [VCV135480](https://www.ncbi.nlm.nih.gov/clinvar/variation/135480/) |

**All HGVS expressions:** `LRG_472:g.18202C>T`, `LRG_472t1:c.736C>T`, `NC_000003.11:g.14206971G>A`, `NC_000003.12:g.14165471G>A`, `NG_011763.1:g.18202C>T`, `NM_001354726.2:c.157C>T`, `NM_001354727.2:c.736C>T`, `NM_001354729.2:c.718C>T`, `NM_001354730.2:c.736C>T`, `NM_004628.5:c.736C>T`, `NR_148950.2:n.769C>T`, `NR_148951.2:n.645C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1255)
- REVEL 0.067 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.451 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.305, GERP 1.68, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 15.15**. 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 0.97** across the covering region of the MANE Select transcript (14,145,944–14,178,568), spanning 32,624 bp. Chi-square p 0.33. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.0134%** (afr) · FAF95 0.00724% · FAF99 0.00551% · 10/74,804 in the highest group · 12/1,604,056 alleles overall — ultra-rare (popmax 0.0134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0134% | 7,480 |
| East Asian | 0.00224% | 44,622 |
| European (non-Finnish) | 8.51e-05% | 1,175,262 |

*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}

**XPC** population constraint: LOEUF 1.023, pLI 1.2517e-20, missense-Z 0.46534. *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):

- **xeroderma pigmentosum group C** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 67.67, 40% of residues very-high.

**18 experimental structure(s)** (PDB): [28JM](https://www.rcsb.org/structure/28JM), [28JS](https://www.rcsb.org/structure/28JS), [28JV](https://www.rcsb.org/structure/28JV), [28KE](https://www.rcsb.org/structure/28KE), [2A4J](https://www.rcsb.org/structure/2A4J), [2GGM](https://www.rcsb.org/structure/2GGM).

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

*Describes the biological roles of XPC (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:** XPC's established molecular role includes damaged DNA binding.


### Pathways affected {#pathways}

XPC participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [DNA Damage Recognition in GG-NER](https://reactome.org/content/detail/R-HSA-5696394) | curated |
| [Formation of Incision Complex in GG-NER](https://reactome.org/content/detail/R-HSA-5696395) | curated |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | curated |

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

**Molecular function:** damaged DNA binding, single-stranded DNA binding, transcription coactivator activity, protein-containing complex binding, DNA damage sensor activity.

**Biological process:** nucleotide-excision repair, positive regulation of DNA-templated transcription, UV-damage excision repair, regulation of mitotic cell cycle phase transition.

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2017-11-02.

**Submitter consensus:** conflicting (1 not provided, 1 Uncertain significance).

**Submission history:** 2 submissions (2013–2017); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ITMI | not provided | no classification provided | reference population | 2013-09-19 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-11-02 |

## Associated conditions {#conditions}

[xeroderma pigmentosum group C](https://sugi.bio/atlas/disease/xeroderma-pigmentosum-group-c/).

**Reported phenotype names (ClinVar):** Xeroderma pigmentosum, group C, not specified, AllHighlyPenetrant, XPC-Related Xeroderma Pigmentosum, Xeroderma pigmentosum, complementation group C, XERODERMA PIGMENTOSUM III, XP, GROUP C.

## Similar variants {#similar}

Related XPC variant pages (same residue, condition, or type): [XPC c.104-2A>G](/variant/xpc-c-104-minus-2a-g), [XPC c.1872+1G>A](/variant/xpc-c-1872-plus-1g-a), [XPC c.1872+1G>C](/variant/xpc-c-1872-plus-1g-c), [XPC c.2033+1G>A](/variant/xpc-c-2033-plus-1g-a), [XPC c.2251-1G>C](/variant/xpc-c-2251-minus-1g-c), [XPC c.2420+2T>C](/variant/xpc-c-2420-plus-2t-c), [XPC c.299+1G>A](/variant/xpc-c-299-plus-1g-a), [XPC c.413-24A>G](/variant/xpc-c-413-minus-24a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 135480). 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.*