# NM_024099.5(LBHD1):c.185T>C (p.Val62Ala)

https://sugi.bio/variant/lbhd1-p-val62ala

## Summary

**LBHD1 p.Val62Ala (c.185T>C)** is classified **Uncertain significance** in LBHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely benign (0.3075); Very rare (popmax 0.00288%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00288%, nfe)

## For patients & families {#patients}

This is a change in the LBHD1 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 | [LBHD1](https://sugi.bio/atlas/gene/LBHD1/) |
| Protein change (HGVS p.) | p.Val62Ala |
| Coding change (HGVS c.) | c.185T>C |
| MANE Select transcript | [NM_024099](https://www.ncbi.nlm.nih.gov/nuccore/NM_024099) |
| Variant type | single nucleotide variant |
| Location | chr11:62669769-62669769 (GRCh38) |
| ClinVar | [VCV4545915](https://www.ncbi.nlm.nih.gov/clinvar/variation/4545915/) |

**All HGVS expressions:** `NC_000011.10:g.62669769A>G`, `NC_000011.9:g.62437241A>G`, `NG_041802.1:g.3116A>G`, `NM_001367940.2:c.263T>C`, `NM_001367941.2:c.185T>C`, `NM_001394596.1:c.353T>C`, `NM_001394599.1:c.677T>C`, `NM_001394601.1:c.508+1471T>C`, `NM_001394604.1:c.260T>C`, `NM_001394606.1:c.184+1795T>C`, `NM_001394607.1:c.91+1471T>C`, `NM_001394609.1:c.185T>C`, `NM_001394611.1:c.185T>C`, `NM_001394612.1:c.185T>C`, `NM_024099.5:c.185T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3075)
- REVEL 0.19 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.068 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.463, GERP 0.519, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **V88A** vs ClinVar **V62A**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 15.8**. 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 1.08** across the covering region of the MANE Select transcript (62,663,132–62,670,031), spanning 6,899 bp. Chi-square p 0.13. 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 (A>T, Δ0.27 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 **0.00288%** (nfe) · FAF95 0.00207% · FAF99 0.00183% · 34/1,180,042 in the highest group · 39/1,461,892 alleles overall — very rare (popmax 0.00288%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,628 |
| European (non-Finnish) (grpmax) | 0.00288% | 34,707 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,036 |

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}

**LBHD1** population constraint: LOEUF 1.281, pLI 5.6594e-09, missense-Z -0.22034. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **62** lies in the lbh domain.

AlphaFold model confidence (whole protein): pLDDT 49.51, 0% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-01.

**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 | 2025-10-01 |

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

## Similar variants {#similar}

Related LBHD1 variant pages (same residue, condition, or type): [UQCC3 p.Arg48Lys](/variant/uqcc3-p-arg48lys), [UQCC3 p.Glu52Ala](/variant/uqcc3-p-glu52ala), [UQCC3 c.121-11C>T](/variant/uqcc3-c-121-minus-11c-t), [UQCC3 c.-399G>T](/variant/uqcc3-c-minus-399g-t), [UQCC3 p.Gly86Ser](/variant/uqcc3-p-gly86ser), [UQCC3 p.Gly89Ser](/variant/uqcc3-p-gly89ser), [UQCC3 p.Thr69Ile](/variant/uqcc3-p-thr69ile), [UQCC3 p.Trp76Gly](/variant/uqcc3-p-trp76gly).

### 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 4545915). 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.*