# NM_025184.4(EFHC2):c.1565G>A (p.Arg522His)

https://sugi.bio/variant/efhc2-p-arg522his

## Summary

**EFHC2 p.Arg522His (c.1565G>A)** is classified **Uncertain significance** in EFHC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.07); Ultra-rare (popmax 0.0103%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs772087258 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0103%, nfe)

## For patients & families {#patients}

This is a change in the EFHC2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [EFHC2](https://sugi.bio/atlas/gene/EFHC2/) |
| Protein change (HGVS p.) | p.Arg522His |
| Coding change (HGVS c.) | c.1565G>A |
| MANE Select transcript | [NM_025184](https://www.ncbi.nlm.nih.gov/nuccore/NM_025184) |
| dbSNP | [rs772087258](https://www.ncbi.nlm.nih.gov/snp/rs772087258/) |
| Variant type | single nucleotide variant |
| Location | chrX:44232536-44232536 (GRCh38) |
| ClinVar | [VCV2262551](https://www.ncbi.nlm.nih.gov/clinvar/variation/2262551/) |

**All HGVS expressions:** `NC_000023.10:g.44091782C>T`, `NC_000023.11:g.44232536C>T`, `NG_021391.1:g.116143G>A`, `NG_021391.2:g.116136G>A`, `NM_025184.4:c.1565G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.07)
- REVEL 0.186 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.699 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.336, GERP -6.27 — weakly conserved position
- CADD: **PHRED 0.08**. 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 0.91** across the covering region of the MANE Select transcript (44,148,798–44,343,588), spanning 194,790 bp. Chi-square p 0.037. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.22 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0103%** (nfe) · FAF95 0.00857% · FAF99 0.00794% · 91/880,127 in the highest group · 94/1,181,308 alleles overall — ultra-rare (popmax 0.0103%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0103% | 9,672 |
| Remaining individuals (not grpmax-eligible) | 0.0043% | 23,239 |
| African / African-American | 0.00177% | 56,603 |

*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.*

## Protein context {#protein}

Residue **522** lies in the dm10 3 domain.

AlphaFold model confidence (whole protein): pLDDT 79.83, 17% of residues very-high.

**4 experimental structure(s)** (PDB): [2Z13](https://www.rcsb.org/structure/2Z13), [2Z14](https://www.rcsb.org/structure/2Z14), [7UNG](https://www.rcsb.org/structure/7UNG), [8J07](https://www.rcsb.org/structure/8J07).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-05.

**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 | 2025-05-05 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related EFHC2 variant pages (same residue, condition, or type): [EFHC2 p.Glu506Lys](/variant/efhc2-p-glu506lys), [EFHC2 p.Glu507Gln](/variant/efhc2-p-glu507gln), [EFHC2 p.Ala549Gly](/variant/efhc2-p-ala549gly), [EFHC2 p.Ala697Ser](/variant/efhc2-p-ala697ser), [EFHC2 p.Arg133His](/variant/efhc2-p-arg133his), [EFHC2 p.Arg135Gln](/variant/efhc2-p-arg135gln), [EFHC2 p.Arg135Trp](/variant/efhc2-p-arg135trp), [EFHC2 p.Arg163Gln](/variant/efhc2-p-arg163gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 2262551). 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.*