# NM_024734.4(CLMN):c.2911C>T (p.Leu971Phe)

https://sugi.bio/variant/clmn-p-leu971phe

## Summary

**CLMN p.Leu971Phe (c.2911C>T)** is classified **Likely benign** in CLMN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: likely benign (0.0563); Very rare (popmax 0.000169%, nfe).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the CLMN 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 | [CLMN](https://sugi.bio/atlas/gene/CLMN/) |
| Protein change (HGVS p.) | p.Leu971Phe |
| Coding change (HGVS c.) | c.2911C>T |
| MANE Select transcript | [NM_024734](https://www.ncbi.nlm.nih.gov/nuccore/NM_024734) |
| Variant type | single nucleotide variant |
| Location | chr14:95191662-95191662 (GRCh38) |
| ClinVar | [VCV3493814](https://www.ncbi.nlm.nih.gov/clinvar/variation/3493814/) |

**All HGVS expressions:** `NC_000014.8:g.95657999G>A`, `NC_000014.9:g.95191662G>A`, `NM_024734.4:c.2911C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0563)
- REVEL 0.15 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.443 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.333, GERP -4.86 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.368**. 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 0.94** across the covering region of the MANE Select transcript (95,191,567–95,319,792), spanning 128,225 bp. Chi-square p 0.024. 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, Δ0.37 donor 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 **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,996 in the highest group · 2/1,461,384 alleles overall — very rare (popmax 0.000169%, nfe).

*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}

**CLMN** population constraint: LOEUF 0.755, pLI 2.3208e-10, missense-Z 1.3112. *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 52.84, 18% of residues very-high.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-10.

**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 | 2024-11-10 |

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

## Similar variants {#similar}

Related CLMN variant pages (same residue, condition, or type): [CLMN c.2511+10C>T](/variant/clmn-c-2511-plus-10c-t), [CLMN c.886-4G>T](/variant/clmn-c-886-minus-4g-t), [CLMN p.Asp592=](/variant/clmn-p-asp592), [CLMN p.Glu276Lys](/variant/clmn-p-glu276lys), [CLMN p.Glu357Lys](/variant/clmn-p-glu357lys), [CLMN p.Glu771Ala](/variant/clmn-p-glu771ala), [CLMN p.His518=](/variant/clmn-p-his518), [CLMN p.Ile900Phe](/variant/clmn-p-ile900phe).

### 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 3493814). 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.*