# NM_001040025.3(ARL16):c.374C>T (p.Thr125Met)

https://sugi.bio/variant/arl16-p-thr125met

## Summary

**ARL16 p.Thr125Met (c.374C>T)** is classified **Likely benign** in ARL16 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-11). AlphaMissense: likely benign (0.0709); Very rare (popmax 0.00356%, nfe).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00356%, nfe)

## For patients & families {#patients}

This is a change in the ARL16 gene that is classified as likely benign — not considered disease-causing, 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 | [ARL16](https://sugi.bio/atlas/gene/ARL16/) |
| Protein change (HGVS p.) | p.Thr125Met |
| Coding change (HGVS c.) | c.374C>T |
| MANE Select transcript | [NM_001040025](https://www.ncbi.nlm.nih.gov/nuccore/NM_001040025) |
| Variant type | single nucleotide variant |
| Location | chr17:81681856-81681856 (GRCh38) |
| ClinVar | [VCV3430110](https://www.ncbi.nlm.nih.gov/clinvar/variation/3430110/) |

**All HGVS expressions:** `NC_000017.10:g.79648886G>A`, `NC_000017.11:g.81681856G>A`, `NG_051248.1:g.7069C>T`, `NM_001040025.3:c.374C>T`, `NM_001329608.2:c.233C>T`, `NM_001329609.2:c.188C>T`, `NR_138058.2:n.603C>T`, `NR_138059.1:n.261C>T`, `NR_138060.1:n.560C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0709)
- REVEL 0.061 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.702 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.364, GERP -4.06 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **T149M** vs ClinVar **T125M**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 1.228**. 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 1.12** across the covering region of the MANE Select transcript (81,681,711–81,683,753), spanning 2,042 bp. Chi-square p 0.081. 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, Δ0.36 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 **0.00356%** (nfe) · FAF95 0.00267% · FAF99 0.00236% · 42/1,179,746 in the highest group · 45/1,612,762 alleles overall — very rare (popmax 0.00356%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00356% | 28,089 |
| African / African-American | 0.00267% | 37,430 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,436 |

*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}

**ARL16** population constraint: LOEUF 1.929, pLI 5.3501e-13, missense-Z -0.63283. *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 86.91, 75% of residues very-high.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-11.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-11 |

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

## Similar variants {#similar}

Related ARL16 variant pages (same residue, condition, or type): [ARL16 c.-41G>T](/variant/arl16-c-minus-41g-t), [ARL16 c.-20C>A](/variant/arl16-c-minus-20c-a), [ARL16 c.-3G>A](/variant/arl16-c-minus-3g-a), [ARL16 p.Ala108Gly](/variant/arl16-p-ala108gly), [ARL16 p.Ala152Thr](/variant/arl16-p-ala152thr), [ARL16 p.Ala167Val](/variant/arl16-p-ala167val), [ARL16 p.Ala7Pro](/variant/arl16-p-ala7pro), [ARL16 p.Arg153Cys](/variant/arl16-p-arg153cys).

### 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 3430110). 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.*