# NM_003741.4(CHRD):c.2057C>T (p.Pro686Leu)

https://sugi.bio/variant/chrd-p-pro686leu

## Summary

**CHRD p.Pro686Leu (c.2057C>T)** is classified **Uncertain significance** in CHRD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-27). AlphaMissense: likely benign (0.0893); Very rare (popmax 0.00337%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1382169691 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00337%, amr)

## For patients & families {#patients}

This is a change in the CHRD 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 | [CHRD](https://sugi.bio/atlas/gene/CHRD/) |
| Protein change (HGVS p.) | p.Pro686Leu |
| Coding change (HGVS c.) | c.2057C>T |
| MANE Select transcript | [NM_003741](https://www.ncbi.nlm.nih.gov/nuccore/NM_003741) |
| dbSNP | [rs1382169691](https://www.ncbi.nlm.nih.gov/snp/rs1382169691/) |
| Variant type | single nucleotide variant |
| Location | chr3:184386616-184386616 (GRCh38) |
| ClinVar | [VCV3144548](https://www.ncbi.nlm.nih.gov/clinvar/variation/3144548/) |

**All HGVS expressions:** `NC_000003.11:g.184104404C>T`, `NC_000003.12:g.184386616C>T`, `NG_029559.1:g.11544C>T`, `NM_001304472.2:c.2057C>T`, `NM_001304473.2:c.947C>T`, `NM_001304474.2:c.947C>T`, `NM_003741.4:c.2057C>T`, `NR_130747.2:n.2224C>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** (0.0893)
- REVEL 0.029 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.485 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.811, GERP -2.69, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 14.41**. 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 0.92** across the covering region of the MANE Select transcript (184,380,319–184,389,419), spanning 9,100 bp. Chi-square p 0.0047. 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, Δ0.51 acceptor 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 **0.00337%** (amr) · FAF95 0.000559% · FAF99 0.000211% · 2/59,368 in the highest group · 15/1,606,962 alleles overall — very rare (popmax 0.00337%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00482% | 20,729 |
| Admixed American (grpmax) | 0.00337% | 29,684 |
| South Asian | 0.0022% | 45,378 |
| European (non-Finnish) | 0.000679% | 147,348 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CHRD** population constraint: LOEUF 0.763, pLI 1.2755e-13, missense-Z 0.72449. *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):

- **congenital heart disease** — Limited (AR)

## Protein context {#protein}

Residue **686** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 73.95, 26% of residues very-high.

**3 experimental structure(s)** (PDB): [9IGM](https://www.rcsb.org/structure/9IGM), [9QVV](https://www.rcsb.org/structure/9QVV), [9RD6](https://www.rcsb.org/structure/9RD6) — incl. mutant structure 9QVV.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-27.

**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 | 2023-10-27 |

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

## Similar variants {#similar}

Related CHRD variant pages (same residue, condition, or type): [CHRD p.Gln608=](/variant/chrd-p-gln608), [CHRD p.Gly387Ser](/variant/chrd-p-gly387ser), [CHRD p.Pro772=](/variant/chrd-p-pro772), [CHRD p.Thr301=](/variant/chrd-p-thr301), [CHRD p.Thr457Ser](/variant/chrd-p-thr457ser), [CHRD p.Ala251Glu](/variant/chrd-p-ala251glu), [CHRD p.Ala251Thr](/variant/chrd-p-ala251thr), [CHRD p.Ala27Pro](/variant/chrd-p-ala27pro).

### 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 3144548). 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.*