# NM_001198961.2(ECHDC2):c.718C>T (p.Arg240Trp)

https://sugi.bio/variant/echdc2-p-arg240trp

## Summary

**ECHDC2 p.Arg240Trp (c.718C>T)** is classified **Uncertain significance** in ECHDC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.2328); Very rare (popmax 0.00538%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00538%, afr)

## For patients & families {#patients}

This is a change in the ECHDC2 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 | [ECHDC2](https://sugi.bio/atlas/gene/ECHDC2/) |
| Protein change (HGVS p.) | p.Arg240Trp |
| Coding change (HGVS c.) | c.718C>T |
| MANE Select transcript | [NM_001198961](https://www.ncbi.nlm.nih.gov/nuccore/NM_001198961) |
| Variant type | single nucleotide variant |
| Location | chr1:52899209-52899209 (GRCh38) |
| ClinVar | [VCV4246361](https://www.ncbi.nlm.nih.gov/clinvar/variation/4246361/) |

**All HGVS expressions:** `NC_000001.10:g.53364881G>A`, `NC_000001.11:g.52899209G>A`, `NM_001198961.2:c.718C>T`, `NM_001198962.1:c.610-1725C>T`, `NM_001319958.2:c.487C>T`, `NM_018281.4:c.625C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2328)
- REVEL 0.733 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -10.655 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 1.163, GERP -2.22, phastCons 0.936 — weakly conserved position
- CADD: **PHRED 27.9**. 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 0.98** across the covering region of the MANE Select transcript (52,896,523–52,921,673), spanning 25,150 bp. Chi-square p 0.66. 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 (G>C, Δ0.26 acceptor loss), 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 **0.00538%** (afr) · FAF95 0.00176% · FAF99 0.00105% · 4/74,392 in the highest group · 7/1,613,424 alleles overall — very rare (popmax 0.00538%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00538% | 18,598 |
| East Asian | 0.00223% | 44,826 |
| South Asian | 0.0011% | 91,070 |
| European (non-Finnish) | 8.47e-05% | 1,180,034 |

*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}

**ECHDC2** population constraint: LOEUF 1.033, pLI 1.241e-07, missense-Z 0.77383. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.28, 91% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-26.

**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 | 2025-08-26 |

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

## Similar variants {#similar}

Related ECHDC2 variant pages (same residue, condition, or type): [ECHDC2 p.Ala105Val](/variant/echdc2-p-ala105val), [ECHDC2 p.Ala131Val](/variant/echdc2-p-ala131val), [ECHDC2 p.Ala152Thr](/variant/echdc2-p-ala152thr), [ECHDC2 p.Ala201Gly](/variant/echdc2-p-ala201gly), [ECHDC2 p.Ala20Pro](/variant/echdc2-p-ala20pro), [ECHDC2 p.Ala20Thr](/variant/echdc2-p-ala20thr), [ECHDC2 p.Ala210Thr](/variant/echdc2-p-ala210thr), [ECHDC2 p.Ala219Thr](/variant/echdc2-p-ala219thr).

### 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 4246361). 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.*