# NM_177977.3(HAP1):c.496G>C (p.Val166Leu)

https://sugi.bio/variant/hap1-p-val166leu

## Summary

**HAP1 p.Val166Leu (c.496G>C)** is classified **Uncertain significance** in HAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). AlphaMissense: likely benign (0.2616); Very rare (popmax 0.00223%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the HAP1 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 | [HAP1](https://sugi.bio/atlas/gene/HAP1/) |
| Protein change (HGVS p.) | p.Val166Leu |
| Coding change (HGVS c.) | c.496G>C |
| MANE Select transcript | [NM_177977](https://www.ncbi.nlm.nih.gov/nuccore/NM_177977) |
| Variant type | single nucleotide variant |
| Location | chr17:41732772-41732772 (GRCh38) |
| ClinVar | [VCV3856746](https://www.ncbi.nlm.nih.gov/clinvar/variation/3856746/) |

**All HGVS expressions:** `LRG_401:g.58941G>C`, `NC_000017.10:g.39889024C>G`, `NC_000017.11:g.41732772C>G`, `NG_009090.2:g.58941G>C`, `NM_001079870.1:c.496G>C`, `NM_001079871.1:c.496G>C`, `NM_001367459.1:c.496G>C`, `NM_001367460.1:c.496G>C`, `NM_001367461.1:c.496G>C`, `NM_001367462.1:c.496G>C`, `NM_177977.3:c.496G>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** (0.2616)
- REVEL 0.029 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.027 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -0.454, GERP 0.973 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.251**. 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 1.05** across the covering region of the MANE Select transcript (41,724,704–41,734,634), spanning 9,930 bp. Chi-square p 0.16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.11**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,864 in the highest group · 1/1,612,700 alleles overall — very rare (popmax 0.00223%, eas).

*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}

**HAP1** population constraint: LOEUF 1.31, pLI 6.4327e-17, missense-Z -0.1706. *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 **166** lies in the hap1 n-terminal domain.

AlphaFold model confidence (whole protein): pLDDT 64.28, 27% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-24.

**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 | 2025-01-24 |

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

## Similar variants {#similar}

Related HAP1 variant pages (same residue, condition, or type): [HAP1 p.Arg106Pro](/variant/hap1-p-arg106pro), [HAP1 p.Cys25Tyr](/variant/hap1-p-cys25tyr), [HAP1 p.Gly604Arg](/variant/hap1-p-gly604arg), [HAP1 p.Ile496Val](/variant/hap1-p-ile496val), [HAP1 p.Leu348=](/variant/hap1-p-leu348), [HAP1 p.Ser616Ter](/variant/hap1-p-ser616ter), [HAP1 p.Thr441Met](/variant/hap1-p-thr441met), [HAP1 p.Thr66Ala](/variant/hap1-p-thr66ala).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3856746). 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.*